Benzamide derivatives and their use as ApoB-100 secretion inhibitors

ABSTRACT

The invention relates to therapeutic benzamide compounds of formula (I)                    
     wherein A, X, Z, R 1 , Y, R 2 , R 3 , are as defined herein, and physiologically acceptable salts, solvates or derivatives thereof. The present invention also provides pharmaceutical compositions, processes for the preparation of compounds of formula (I) and their use in the treatment of conditions mediated by ApoB-100 regulation.

CROSS-REFERENCES TO RELATED APPLICATIONS

This application is a Rule 371 Application of PCT Application No.EP99/09320, filed Dec. 1, 1999, which claims priority to GB ApplicationSerial No. 9826412.0, filed Dec. 3, 1998.

This invention relates to novel compounds which inhibit hepaticproduction of apoprotein B-100 (apoB-100), and to processes for theirpreparation, pharmaceutical compositions containing them and theirmedical use.

ApoB-100 is the main protein component of low densitylipoprotein-cholesterol (LDL-C). High LDL-C plasmatic levels are a majorrisk factor for atherosclerosis and coronary, artery diseases. ApoB-100plasmatic levels correlate with LDL-C plasmatic levels and alsoconstitute a cardiovascular risk factor in themselves. ApoB-100 isexclusively produced by hepatocytes and reducing hepatic production ofApoB-100 should induce a decrease of LDL-C plasmatic levels.

Compounds having ApoB-100 inhibition properties have been described inWO96/40640, which is incorporated herein by reference.

DETAILED DESCRIPTION OF THE INVENTION

The present invention provides a compound of formula (I)

wherein

A represents N or CH;

X is selected from the following groups:

(i) —C₁₋₆alkylene-, optionally containing one or two double bonds andoptionally substituted by one or more hydroxy, C₁₋₆alkyl, C₁₋₆alkoxy,C₁₋₆acyl or C₁₋₆acyloxy groups,

(ii) oxo, sulfonyl, thioxo,

(iii)—C₁₋₆alkylenecarbonyl-,—C₁₋₆alkylenesulfonyl-,—C₁₋₆alkylenethioxo-,

(iv) —C₂₋₆alkyleneoxy-, —C₂₋₆alkylenethio-, —C₂₋₆alkylene(N—H orN—C₁₋₆alkyl)amino-,

(v) —C₁₋₆alkylenecarboxy-, —C₁₋₆alkylenethioamido-, —C₁₋₆alkylene(N—H orN—C₁₋₆alkyl)carboxamido-, and

(vi) —C₂₋₆alkyleneoxycarbonyl-, —C₂₋₆alkylenethiocarbonyl-,—C₂₋₆alkylene(N—H or N—C₁₋₆alkyl)aminocarbonyl-;

Z represents a direct link or —C₁₋₆alkylene-, optionally containing onedouble bond and optionally substituted by one or more hydroxy,C₁₋₆alkyl, C₁₋₆alkoxy, C₁₋₆acyl or C₁₋₆acyloxy groups;

R¹ is selected from the following groups:

(i) hydrogen, C₁₋₃perfluoroalkyl,

(ii) C₆₋₁₀ aryl, C₃₋₈cycloalkyl and fused benz derivatives thereof,C₇₋₁₀polycycloalkyl, C₄₋₈cycloalkenyl, C₇₋₁₀polycycloalkenyl,

(iii) a heterocyclyl selected from the group consisting of monocyclicradicals and fused polycyclic radicals, wherein said, radicals contain atotal of from 5-14 ring atoms, wherein said radicals contain a total offrom 1-4 ring heteroatoms independently selected from oxygen, nitrogenand sulfur, and wherein individual rings of said radicals may beindependently saturated, partially unsaturated, or aromatic, and

(iv) where either X is C₁₋₆alkylene and Z is a direct link, or Z isC₁₋₆alkylene, R¹ additionally may represent a halogen, cyano, nitro orC₁₋₆acyl group,

 wherein, when R¹ contains one or more rings, said rings may eachindependently bear 0 to 4 substituents independently selected from

(i) halogen, hydroxy, cyano, nitro, formyl, C₁₋₆alkylsulfonylamino,

(ii) C₁₋₆alkyl, C₃₋₈cycloalkyl, C₁₋₃perfuoroalkyl,

(iii) C₁₋₆alkoxy, methylenedioxy, C₁₋₃perfuoroalkoxy, C₁₋₆alkylthio,

(iv) amino, C₁₋₆alkylamino, di-C₁₋₆alkylamino,

(v) phenyl, phenoxy, phenylthio, halophenylthio, benzyl, benzyloxy,

(vi) hydroxycarbonyl,C₁₋₆alkoxycarbonyl,

(vii) aminocarbonyl, C₁₋₆alkylaminocarbonyl, di-C₁₋₆alkylaminocarbonyl,di-C₁₋₆alkylaminocarbonylC₁₋₆oxy, C₁₋₃perfluoroalkylaminocarbonyl,

(viii) C₁₋₆acyl, C₁₋₆acyloxy, C₁₋₆acyloxyC₁₋₆alkyl, C₁₋₆acylamino, and

(ix) an aromatic heterocyclyl consisting of monocyclic radicals, whereinsaid radicals contain 5-6 ring atoms, wherein said radicals contain atotal of from 1-4 ring heteroatoms independently selected from oxygen,nitrogen and sulfur, and where each of the said heterocyclyl groups isoptionally substituted by one or more groups independently selected fromhalogen, C₁₋₄alkyl, C₁₋₄alkoxy, C₁₋₃perfuoroalkyl andC₁₋₃perfuoroalkoxy;

Y represents a direct or oxy link, —C₁₋₆alkylene-, -oxyC₁₋₆alkylene- ora heterocyclyl consisting of monocyclic radicals, wherein said radicalscontain 5 ring atoms, and wherein said radicals contain a total of from1-4 ring heteroatoms independently selected from oxygen, nitrogen andsulfur and wherein the ring may be independently saturated, partiallyunsaturated, or aromatic;

R² represents phenyl, C₃₋₈cycloalkyl, or a heterocyclyl consisting ofmonocyclic radicals, wherein said radicals contain a total of from 5-6ring atoms, wherein said radicals contain a total of from 1-4 ringheteroatoms independently selected from oxygen, nitrogen and sulfur,wherein the ring may be independently saturated, partially unsaturated,or aromatic, and where each R² is optionally substituted by one or moregroups independently selected from halogen, C₁₋₄alkyl, C₁₋₄alkoxy,C₃₋₈cycloalkyl, C₁₋₃perfuoroalkyl, C₁₋₃perfuoroalkoxy, hydroxycarbonyl,C₁₋₆alkoxycarbonyl, cyano, nitro, C₁₋₄alkylaminosulfonyl;

R³ represents hydrogen or one or more groups independently selected fromhalogen, C₁₋₄alkyl, C₁₋₄alkoxy, C₁₋₃ perfluoroalkyl or C₁₋₃perfluoroalkoxy;

or a physiologically acceptable salt, solvate or derivative thereof.

Suitable physiologically acceptable salts of the compounds of generalformula (I) include acid addition salts formed with pharmaceuticallyacceptable organic and inorganic acids for example, citrates,hydrochlorides, hydrobromides, or sulphates. Particularly preferredsalts are citrates or hydrochloride salts.

The solvates may, for example, be hydrates.

References hereinafter to a compound according to the invention includeboth compounds of formula (I) and their physiologically acceptable saltstogether with physiologically acceptable solvates.

Referring to the general formula (I), alkyl, alkylene and alkoxy includeboth straight and branched chain saturated hydrocarbon groups. Examplesof alkyl groups include methyl and ethyl groups, examples of alkylenegroups include methylene and ethylene groups, whilst examples of alkoxygroups include methoxy and ethoxy groups.

Referring to general formula (I), a halogen atom may be a fluorine,chlorine, bromine or iodine atom.

Referring to the general formula (I), reference to heterocyclyl, unlessotherwise defined, means any single ring or fused ring system containingat least one ring heteroatom independently selected from O, N and S.Thus, a polycyclic fused ring system containing one or more carbocyclicfused saturated, partially unsaturated, or aromatic rings (usually benzrings) is within the definition of heterocyclyl so long as the systemalso contains at least one fused ring which contains at least one of theaforementioned heteroatoms. As a substituent, such heterocyclyls may beattached to the remainder of the molecules from either a carbocyclic(e.g. benz) ring or from a heterocyclic ring.

Referring to the general formula (I), reference to R¹ as containing oneor more rings is intended to mean any single or fused cyclic moiety ormoieties attached to Z. The rings may be carbocyclic or heterocyclic,saturated or partially unsaturated, and aromatic or non-aromatic.

Reference to a polycyclic ring system or radical means that all rings inthe system are fused.

Referring to the general formula (I), aryl means that the ring orsubstituent is carbocyclic and includes phenyl and naphthyl.

Referring to the general formula (I), acyl refers to aliphatic or cyclichydrocarbons attached to a carbonyl group through which the substituentbonds.

Referring to the general formula (I), methylenedioxy refers to ax,x+1-methylenedioxy group, where x and x+1 are integers which representthe substitiution pattern on the ring, e.g. 3,4-methylenedioxy.

Referring to the general formula (I), C₁₋₃perfuoroalkyl orC₁₋₃perfuoroalkoxy includes compounds such as trifluoromethyl andtrifluoromethoxy.

Suitably, the piperazine or piperidine group in formula (I) issubstituted meta or para, most suitably para substituted. Preferably, Arepresents N.

X is suitably —C₁₋₆alkylene-, optionally containing by one double bond,e.g. methylene, ethylene, propylene or but-2-enylene, oxo, sulfonyl,—C₂₋₆alkyleneoxy-, e.g. ethyleneoxy or propyleneoxy, —C₁₋₆alkylenecarboxy-, e.g. methylenecarboxy or —C₁₋₆alkylene(N—H orN—C₁₋₆alkyl)carboxamido-, e.g. methylene(N—H)carboxamido.

X is equally suitably methylene, oxo, or sulfonyl. As a preferredaspect, X is a methylene group.

Z is suitably a direct link or C₁₋₆alkylene, e.g. methylene or ethylene.Z is most suitably a direct link.

R¹ is suitably selected from the following groups

(i) hydrogen, cyano, C₁₋₃perfuoroalkyl, e.g. trifluoromethyl,

(ii) optionally substituted phenyl, where optional substitution iseffected by one or two groups independently selected from C₁₋₆ alkyl,e.g. methyl, cyano, halogen, e.g. fluoro, C₁₋₆alkoxy, e.g. methoxy,C₁₋₃perfuoroalkyl, e.g. trifluoromethyl, hydroxycarbonyl,C₁₋₄alkoxycarbonyl, e.g. methoxycarbonyl, aminocarbonyl, methylenedioxy,nitro, C₁₋₆ acyl, e.g. acetyl, phenyl, or an optionally substitutedaromatic heterocycyl consisiting of monocyclic radicals and fusedpolycyclic radicals, wherein said radicals contain a total of 5 ringatoms, e.g. oxadiazolyl, where optional substitution is effected by C₁₋₄alkyl, e.g. methyl, or C₁₋₃perfluoroalkyl, e.g. trifluoromethyl, or

(iii) an optionally substituted aromatic heterocyclyl consisiting ofmonocyclic radicals and fused polycyclic radicals, wherein said radicalscontain a total of from 5-10 ring atoms, e.g. indolyl, pyrrolyl,thienyl, furanyl, imidazolyl, pyrazolyl, thiazolyl, pyridyl orpyrazinyl, where optional substitution is effected by C₁₋₄alkyl, e.g.methyl, or halogen, e.g. fluorine.

Where R¹ is a substituted phenyl group, substitution is suitably in the3-position.

When R¹ is an optionally substituted aromatic heterocyclyl, R¹ ispreferably an optionally substituted pyrrolyl, where optionalsubstitution is effected by a methyl group. Most preferably, thesubstitution pattern is 2-pyrrolyl.

R¹ is more suitably selected from the following groups

(i) hydrogen,

(ii) substituted phenyl, where substitution is effected by cyano or amethyl substituted oxadiazolyl group, or

(iii) a pyrrolyl group

X—Z is suitably methylene or oxo and R¹ is suitably phenyl or aheterocyclyl, e.g. pyrrolyl, furanyl, C-linked imidazolyl, thienyl,pyrazolyl, thiazolyl, triazolyl, indolyl, pyridyl, N-Me-imidazolyl orpyrazinyl, where each R¹ is optionally substitued by one or more groupsindependently selected from C₁₋₆ alkyl, e.g. methyl, cyano, halogen,e.g. fluoro, C₁₋₆alkoxy, e.g. methoxy, trifluoromethyl, hydroxycarbonyland C₁₋₄alkoxycarbonyl, e.g. methoxycarbonyl.

R¹ is preferably phenyl substituted by 3-cyano.

As a most preferred substitution pattern, —X—Z—R¹ is suitablyaminocarbonylmethyl, pyrrolylmethyl or phenylmethyl substituted by cyanoor methyl-oxadiazole.

Y is suitably a direct link, a 2,5-substituted oxazolyl group, or—(CH₂)_(n)—O—, where n is an integer from 0-3. More suitably, Y is adirect or oxy link. Preferably Y is a direct link.

R² is suitably cyclohexyl, a 5-6 membered aromatic heterocyclyl, e.g.pyrrolyl or pyridyl, or a phenyl group optionally substituted by one ortwo groups independently selected from halogen, e.g. fluoro or chloro,C₁₋₄ alkyl, e.g. methyl, ethyl or isopropyl, C₁₋₄ alkoxy, e.g. methoxy,or trifluoromethyl groups, where substitution is suitably in one or twoof the 2-, 3-, or 4-positions on the phenyl ring. Preferably, R² is aphenyl group substituted by a trifluoromethyl group, most preferably inthe 4-position. Equally preferably, R² is a phenyl group substituted byan isopropyl group, most preferably in the 4-position.

Preferably, Y is a direct link and R² is a phenyl group substituted by atrifluoromethyl or isopropyl group, most preferably in the 4-position.

R³ is suitably hydrogen, halogen, e.g. chlorine, C₁₋₄ alkyl, e.g.methyl, C₁₋₃ perfluoroalkyl, e.g. trifluoromethyl or C₁₋₄ alkoxy e.g.methoxy. R³ is more suitably hydrogen, halogen, e.g. chlorine, C₁₋₄alkyl e.g. methyl or C₁₋₄ alkoxy e.g. methoxy. R³ is preferably ahydrogen, methyl, methoxy or chloro group. R³ is equally preferably ahydrogen, methoxy or chloro group. Substitution is preferably in the 5or 6 position.

Particularly preferred compounds of the invention include those in whicheach variable in Formula (I) is selected from the preferred groups foreach variable. Even more preferable compoundsof the invention includethose where each variable in Formula (I) is selected from the morepreferred or most preferred groups for each variable.

A suitable sub-group of a compound of formula (I) is represented byformula (Ia)

wherein

A is CH or N;

X is suitably C₁₋₆alkylene, optionally containing one double bond, oxo,sulfonyl, —C₂₋₆alkyleneoxy-, —C₁₋₆alkylenecarboxy- or —C₁₋₆alkylene(N—Hor N—C₁₋₆alkyl)carboxamido;

Z represents a direct link or C₁₋₆alkylene;

R¹ represents one of the following groups

(i) hydrogen, C₁₋₃perfuoroalkyl,

(ii) optionally substituted phenyl, where optional substitution iseffected by one or two groups independently selected from C₁₋₆ alkyl,cyano, halogen, C₁₋₆alkoxy, C₁₋₃perfuoroalkyl, hydroxycarbonyl,C₁₋₄alkoxycarbonyl, aminocarbonyl, C₁₋₃perfluoroalkylaminocarbonyl,methylenedioxy, nitro, C₁₋₆ acyl, phenyl, or an optionally substitutedaromatic heterocyclyl consisiting of monocyclic radicals and fusedpolycyclic radicals, wherein said radicals contain a total of 5 ringatoms, where optional substitution is effected by C₁₋₄alkyl, orC₁₋₃perfluoroalkyl,

(iii) an optionally substituted aromatic heterocycyl consisiting ofmonocyclic radicals and fused polycyclic radicals, wherein said radicalscontain a total of from 5-10 ring atoms, where optional substitution iseffected by C₁₋₄alkyl, or C₁₋₃perfluoroalkyl; or

(iv) where either X is C₁₋₆alkylene and Z is a direct link, or Z isC₁₋₆alkylene, R¹ additionally may represent a cyano group;

Y represents a direct or oxy link, a 5-membered aromatic heterocyclylgroup, —C₁₋₆alkylene- or -oxyC₁₋₆alkylene-;

R² represents phenyl, C₃₋₈cycloalkyl, or an aromatic heterocyclecontaining 5-6 ring atoms and 1-4 ring heteroatoms, where each ring isoptionally substituted by one or more groups independently selected fromhalogen, C₁₋₄alkyl, C₁₋₄alkoxy or C₁₋₃perfuoroalkyl;

R³ represents hydrogen, halogen, C₁₋₄alkyl or C₁₋₄alkoxy;

or a physiologically acceptable salt, solvate or derivative thereof.

A further suitable sub-group of a compound of formula (I) is representedby formula (Ib)

wherein

X is methylene, oxo or sulfonyl,

Z is selected from a direct link or NH,

provided that if X is a methylene group, Z is a direct link;

R¹ is selected from the following groups:

(i) hydrogen

(ii) C₁₋₆alkoxy, C₁₋₆alkylthio,

(iii) C₁₋₆alkylamino, di-C₁₋₆alkylamino C₆₋₁₀ arylC₁₋₆alkylamino,provided that Z is not NH,

(iv) unsubstuted vinyl, C₆₋₁₀aryl, C₃₋₈cycloalkyl, C₃₋₈cycoalkenyl,

(v) C₆₋₁₀ aryloxy

(vi) heterocyclyl selected from the group consisting of 5- and6-membered heterocyclic radicals, which may be saturated, partiallysaturated, or aromatic, and the fused benz derivatives thereof, whereinsaid radicals may contain a total of from 1 to 3 ring heteroatomsindependently selected from oxygen, nitrogen and sulfur,

provided that if X is CH₂, R¹ is selected from groups (iv) and (vi)

wherein, when R¹ contains one or more rings, said rings may eachindependently bear 0 to 3 substituents independently selected fromhalogen, hydroxy, cyano, C₁₋₆alkyt, C₁₋₆alkoxy, C₁₋₆alkylaminocarbonyl,di-C₁₋₆alkylamino, di-C₁₋₆alkylaminocarbonyl,di-C₁₋₆alkylaminocarbonylC₁₋₆alkoxy, C₁₋₆acyl, C₁₋₃perfuoroalkoxy,C₁₋₆acyloxy, hydroxycarbonyl and C₁₋₆alkoxycarbonyl;

Y represents a bond, an oxazolyl group, —O—, a —C₁₋₆alkylene- or an—O—C₁₋₆alkylene-group;

R² represents phenyl, C₃₋₈cycloalkyl, or a heterocycle containing 5-6ring atoms and 1-4 ring heteroatoms, where each ring is optionallysubstituted by one or more groups independently selected from halogen,C₁₋₄alkyl, C₁₋₄alkoxy, C₃₋₈cycloalkyl, C₁₋₃perfuoroalkyl,C₁₋₃perfuoroalkoxy, C₁₋₆alkoxycarbonyl, cyano, phenyl, phenoxy, benzyl,benzyloxy;

R³ represents hydrogen or one or two groups independently selected fromhalogen, C₁₋₄alkyl or C₁₋₄alkoxy groups; or a physiologically acceptablesalt, solvate or derivative thereof.

A yet further suitable sub-group of the invention is represented by acompound of formula (Ic)

wherein

X is methylene, oxo or sulfonyl,

R¹ represents phenyl or a 5-6 membered aromatic heterocyclic group, saidgroups being optionally substitued by one or two groups independentlyselected from C₁₋₆ alkyl, cyano, halogen, C₁₋₆ alkoxy, trifluoromethyl,hydroxycarbonyl and C₁₋₆alkoxycarbonyl;

R² represents phenyl substituted by one or two groups independentlyselected from halogen, trifluoromethyl, C₁₋₄alkyl or C₁₋₄alkoxy groups;

R³ represents hydrogen or one or two groups independently selected fromhalogen, C₁₋₄alkyl and C₁₋₄alkoxy groups;

or a physiologically acceptable salt, solvate or derivative thereof.

A yet further suitable sub-group of the invention is represented by acompound of formula (Id)

wherein

R¹ represents phenyl optionally substitued by one or two groupsindependently selected from C₁₋₆ alkyl, cyano, halogen, C₁₋₆ alkoxy,trifluoromethyl, hydroxycarbonyl and C₁₋₆alkoxycarbonyl;

R² represents phenyl substituted by one or two groups independentlyselected from halogen, trifluoromethyl, C₁₋₄alkyl and C₁₋₄alkoxy groups;

R³ represents hydrogen or one or two groups independently selected fromhalogen, C₁₋₄alkyl and C₁₋₄alkoxy groups;

or a physiologically acceptable salt, solvate or derivative thereof.

A yet further suitable sub-group of the invention is represented.by acompound of formula (Ie)

wherein

R¹ is selected from the following groups

(i) aminocarbonyl,

(ii) phenyl, optionally substituted by C₁₋₆alkyl, cyano, halogen,C₁₋₆alkoxy, C₁₋₃perfuoroalkyl, hydroxycarbonyl, C₁₋₄alkoxycarbonyl,aminocarbonyl, methylenedioxy, nitro, C₁₋₆acyl, phenyl, or an optionallysubstituted 5-membered aromatic heterocyclyl, where optionalsubstitution is effected by C₁₋₄alkyl or C₁₋₃perfluoroalkyl, or

(iii) an optionally substituted aromatic heterocycyl consisiting ofmonocyclic radicals and fused polycyclic radicals, wherein said radicalscontain a total of from 5-10 ring atoms, where optional substitution iseffected by C₁₋₄alkyl;

R² represents phenyl, optionally substituted by one or two groupsindependently selected from halogen, C₁₋₃perfluoroalkyl, C₁₋₄alkyl andC₁₋₄alkoxy groups;

R³ represents hydrogen, halogen, C₁₋₄alkyl or C₁₋₄alkoxy;

or a physiologically acceptable salt, solvate or derivative thereof.

It will be clear that references herein to a compound of formula (I)apply equally to a compound of formula (Ia)-(Ie).

Particularly preferred compounds of the invention include those in whicheach variable of formula (I) is selected from the suitable groups foreach variable. Even more preferable compounds of the invention includethose where each variable in formula (I) is selected from the preferredor more preferred groups for each variable.

Suitable compounds according to the invention include:

4′-Trifluoromethyl-biphenyl-2-carboxylic acid[4-[4-(3-cyano-benzyl)-piperazin-1-yl]-phenyl]-amide;

4′-Isopropyl-5-methyl-biphenyl-2-carboxylic acid[4-[4-(3-cyano-benzyl)-piperazin-1-yl]-phenyl]-amide;

4′-Isopropyl-6-methoxy-biphenyl-2-carboxylic acid[4-[4-(3-cyano-benzyl)-piperazin-1-yl]-phenyl]-amide;

4′-Isopropyl-6-methyl-biphenyl-2-carboxylic acid[4-[4-(3-cyano-benzyl)-piperazin-1-yl]-phenyl]-amide;

6-Methyl-4′-trifluoromethyl-biphenyl-2-carboxylic acid[4-[4-(3-cyano-benzyl)-piperazin-1-yl]-phenyl]-amide;

4′-Isopropyl-5-methyl-biphenyl-2-carboxylic acid(4-{3-(3-methyl-[1,2,4]oxadiazol-5-yl)-benzyl]-piperazin-1-yl}-phenyl)-amide;

5-Chloro-4′-isopropyl-biphenyl-2-carboxylic acid[4-[4-(3-cyano-benzyl)-piperazin-1-yl]-phenyl]-amide;

6-Methoxy-4′-trifluoromethyl-biphenyl-2-carboxylic acid[4-[4-(3-cyano-benzyl)-piperazin-1-yl]-phenyl]-amide;

5-Methyl-4′-trifluoromethyl-biphenyl-2-carboxylic acid[4-[4-(3-cyano-benzyl)-piperazin-1-yl]-phenyl]-amide;

5-Chloro-4′-trifluoromethyl-biphenyl-2-carboxylic acid[4-[4-(3-cyano-benzyl)-piperazin-1-yl]-phenyl]-amide;

Biphenyl-2-carboxylic acid(4-[4-(3-cyano-benzyl)-piperazin-1-yl]-phenyl]-amide;

5-Methoxy-biphenyl-2-carboxylic acid[4-[4-(3-cyano-benzyl)-piperazin-1-yl]-phenyl]-amide;

4-Chloro-4′-trifluoromethyl-biphenyl-2-carboxylic acid[4-[4-(3-cyano-benzyl)-piperazin-1-yl]-phenyt]-amide;

N-[4-[4-(3-Cyano-benzyl)-piperazin-1-yl]-phenyl]-2-phenoxy-benzamide;

N-[4-[4-(3-Cyano-benzyl)-piperazin-1-yl]-phenyl]-2-(5-phenyl-oxazol-2-yl)-benzamide;

4′-Isopropyl-biphenyl-2-carboxylic acid[4-[4-(3-cyano-benzyl)-piperazin-1-yl]-phenyl]-amide;

5-Methoxy-4′-trifluoromethyl-biphenyl-2-carbbxylic acid[4-[4-(3-cyano-benzyl)-piperazin-1-yl]-phenyl]-amide;

4-Methyl-4′-trifluoromethyl-biphenyl-2-carboxylic acid[4-[4-(3-cyano-benzyl)-piperazin-1-yl]-phenyl]-amide;

4-Methoxy-4′-trifluoromethyl-biphenyl-2-carboxylic acid[4-[4-(3-cyano-benzyl)-piperazin-1-yl]-phenyl]-amide;

4′-Ethyl-biphenyl-2-carboxylic acid[4-[4-(3-cyano-benzyl)-piperazin-1-yl]-phenyl]-amide;

4′-Methoxy-biphenyl-2-carboxylic acid[4-[4-(3-cyano-benzyl)-piperazin-1-yl]-phenyl]-amide;

3′-Trifluoromethyl-biphenyl-2-carboxylic acid[4-[4-(3-cyano-benzyl)-piperazin-1-yl]-phenyl]-amide;

4′-Fluoro-biphenyl-2-carboxylic acid[4-[4-(3-cyano-benzyl)-piperazin-1-yl]-phenyl]-amide;

3′,4′-Dimethyl-biphenyl-2-carboxylic acid[4-[4-(3-cyano-benzyl)-piperazin-1-yl]-phenyl]-amide;

2′,4′-Dimethyl-biphenyl-2-carboxylic acid[4-[4-(3-cyano-benzyl)-piperazin-1-yl]-phenyl]-amide;

3′,4′-Dimethoxy-biphenyl-2-carboxylic acid[4-[4-(3-cyano-benzyl)-piperazin-1-yl]-phenyl]-amide;

N-[4-[4-(3-Cyano-benzyl)-piperazin-1-yl]-phenyl]-2-(4-trifluoromethyl-benzyloxy)-benzamide;

N-[4-[4-(3-Cyano-benzyl)-piperazin-1-yl]-phenyl]-3-methoxy-2-(4-trifluoromethyl-benzyloxy)-benzamide;

N-[4-[4-(3-Cyano-benzyl)-piperazin-1-yl]-phenyl]-2-(4-fluoro-benzyloxy)-3-methoxy-benzamide;

N-[4-[4-(3-Cyano-benzyl)-piperazin-1-yl]-phenyl]-3-methoxy-2-phenethyloxy-benzamide;

N-[4-[4-(3-Cyano-benzyl)-piperazin-1-yl]-phenyl]-2-(2-cyclohexyl-ethoxy)-3-methoxy-benzamide;

N-[4-[4-(3-Cyano-benzyl)-piperazin-1-yl]-phenyl]-2-(2-cyclohexyl-ethoxy)-benzamide;

N-[4-[4-(3-Cyano-benzyl)-piperazin-1-yl]-phenyl]-3-methoxy-2-(3-phenyl-propoxy)-benzamide

N-4-[4-(3-Cyano-benzyl)-piperazin-1-yl]-phenyl]-2-(4-fluoro-benzyloxy)-benzamide;

4′-Trifluoromethyl-biphenyl-2-carboxylic acid[3-[4-(3-cyano-benzyl)-piperazin-1-yl]-phenyl]-amide;

4′-Trifluoromethyl-biphenyl-2-carboxylic acid[4-(4-carbamoylmethyl-piperazin-1-yl)-phenyl]-amide;

4′-Isopropyl-6-methoxy-biphenyl-2-carboxylic acid[4-(4-carbamoylmethyl-piperazin-1-yl)-phenyl]-amide;

4′-Isopropyl-6-methyl-biphenyl-2-carboxylic acid[4-(4-carbamoylmethyl-piperazin-1-yl)-phenyl]-amide;

6-Methyl-4′-trifluoromethyl-biphenyl-2-carboxylic acid[4-(4-carbamoylmethyl-piperazin-1-yl)-phenyl]-amide

4′-Trifluoromethyl-biphenyl-2-carboxylic acid[4-(4-cyanomethyl-piperazin-1-yl]-phenyl]-amide;

4′-Trifluoromethyl-biphenyl-2-carboxylic acid[4-(4-ethoxycarbonylmethyl-piperazin-1-yl)-phenyl]-amide;

4′-Trifluoromethyl-biphenyl-2-carboxylic acid[4-(4-(2-ethoxy-ethyl)-piperazin-1-yl]-phenyl]-amide;

4′-Trifluoromethyl-biphenyl-2-carboxylic acid[4-(4-(3-hydroxy-propyl)-piperazin-1-yl]-phenyl]-amide;

4′-Trifluoromethyl-biphenyl-2-carboxylic acid[4-(4-(4,4,4-trifluoro-butyl)-piperazin-1-yl]-phenyl]-amide;

4′-Trifluoromethyl-biphenyl-2-carboxylic acid[4-(4-(3-methyl-but-2-enyl)-piperazin-1-yl]-phenyl]-amide;

4′-Trifluoromethyl-biphenyl-2-carboxylic acid[4-(4-(3-cyano-4-fluoro-benzyl)-piperazin-1-yl)-phenyl]-amide;

4′-Trifluoromethyl-biphenyl-2-carboxylic acid[4-(4-(3,4-methylenedioxy-benzyl)-piperazin-1-yl)-phenyl]-amide;

4′-Trifluoromethyl-biphenyl-2-carboxylic acid[4-(4-(3-nitro-benzyl)-piperazin-1-yl)-phenyl]-amide;

4′-Trifluoromethyl-biphenyl-2-carboxylic acid{4-[4-(3-carbamoyl-benzyl)-piperazin-1-yl]-phenyl}-amide;

4′-Trifluoromethyl-biphenyl-2-carboxylic acid[4-[4-(3-methoxy-benzyl)-piperazin-1-yl]-phenyl]-amide;

4′-Trifluoromethyl-biphenyl-2-carboxylic acid[4-[4-(4-fluoro-benzyl)-piperazin-1-yl]-phenyl]-amide;

4′-Trifluoromethyl-biphenyl-2-carboxylic acid[4-[4-(3-fluoro-benzyl)-piperazin-1-yl]-phenyl]-amide;

4′-Trifluoromethyl-biphenyl-2-carboxylic acid[4-(4-benzyl)-piperazin-1-yl]-phenyl]-amide;

4′-Trifluoromethyl-biphenyl-2-carboxylic acid[4-[4-(3-carbomethoxy-benzyl)-piperazin-1-yl]-phenyl]-amide;

4′-Trifluoromethyl-biphenyl-2-carboxylic acid[4-(4-pyridin-4-ylmethyl-piperazin-1 -yl)-phenyl]-amide;

4′-Trifluoromethyl-biphenyl-2-carboxylic acid[4-(4-pyridin-2-ylmethyl-piperazin-1-yl)-phenyl]-amide;

4′-Trifluoromethyl-biphenyl-2-carboxylic acid[4-(4-pyrazin-2-ylmethyl-piperazin-1-yl)-phenyl]-amide;

4′-Trifluoromethyl-biphenyl-2-carboxylic acid[4-(4-thiazol-2-ylmethyl-piperazin-1-yl)-phenyl]-amide;

4′-Trifluoromethyl-biphenyl-2-carboxylic acid[4-[4-(1-methyl-1H-imidazol-2-ylmethyl)-piperazin-1-yl)-phenyl]-amide;

4′-Isopropyl-6-methyl-biphenyl-2-carboxylic acid(4-(4-(3-(3-methyl-[1,2,4]oxadiazol-5-yl)-benzyl)-piperazine-1-yl)-phenyl)-amide;

4′-Trifluoromethyl-biphenyl-2-carboxylic acid[4-(4-(1H-pyrrol-2-ylmethyl)-piperazin-1-yl)-phenyl]-amide;

4′-Isopropyl-5-methyl-biphenyl-2-carboxylic acid[4-(4-(1H-pyrrol-2-ylmethyl)-piperazin-1-yl)-phenyl]-amide;

5-Methyl-4′-trifluoromethyl-biphenyl-2-carboxylic acid[4-(4-(1H-pyrrol-2-ylmethyl)-piperazin-1-yl)-phenyl]-amide;

4′-Trifluoromethyl-biphenyl-2-carboxylic acid[4-(4-propyl-piperazin-1-yl)-phenyl]-amide;

4′-Trifluoromethyl-biphenyl-2-carboxylic acid[4-(4-(3-acetyl-benzyl)-piperazin-1-yl)-phenyl]-amide;

4′-Trifluoromethyl-biphenyl-2-carboxylic acid[4-(4-furan-2-ylmethyl-piperazin-1-yl)-phenyl]-amide;

4′-Isopropyl-6-methoxy-biphenyl-2-carboxylic acid[4-(4-(1H-pyrrol-2-ylmethyl)-piperazin-1-yl)-phenyl]-amide;

4′-Trifluoromethyl-biphenyl-2-carboxylic acid[4-(4-(1-methy)-1H-pyrrol-2-ylmethyl)-piperazin-1-yl)-phenyl]-amide;

4′-Trifluoromethyl-biphenyl-2-carboxytic acid[4-(4-thiophen-2-ylmethyl-piperazin-1-yl)-phenyl]-amide;

4′-Trifluoromethyl-biphenyl-2-carboxylic acid{4-[4-(1H-pyrazole-3-ylmethyl)-piperazine-1-yl]-phenyl}amide;

4′-Trifluoromethyl-biphenyl-2-carboxylic acid[4-(4-thiophen-3-ylmethyl-piperazin-1-yl)-phenyl]-amide;

4′-Trifluoromethyl-biphenyl-2-carboxylic acid{4-[4-(5-fluoro-1H-indol-3-ylmethyl)-piperazin-1-yl]-pheny}-amide;

4′-Isopropyl-6-methoxy-biphenyl-2-carboxylic acid(4-(4-(3-(3-methyl-[1,2,4]oxadiazol-5-yl)-benzyl)-piperazine-1-yl)-phenyl)-amide;

4′-Trifluoromethyl-biphenyl-2-carboxylic acid(4-{4-[3-(5-trifluoromethyl-[1,2,4]oxadiazol-3-yl)-benzyl]-piperazin-1-yl}-phenyl)-amide;(4-{4-[(4′-Trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-piperazin-1-yl]-aceticacid;

4′-trifluoromethyl-biphenyl-2-carboxylic acid[4-(4-{[(biphenyl-3-ylmethyl)-carbamoyl]-methyl}-piperazin-1-yl)-phenyl]-amide;

3-(4-{4-[(4′-Trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-piperazin-1-ylmethyl)-benzoic acid;

4′-Trifluoromethyl-biphenyl-2-carboxylic acid(4-{4-[3-(2,2,2-trifluoro-ethylcarbamoyl)-benzyl]-piperazin-1-yl}-phenyl)-amide;

4′-Trifluoromethyl-biphenyl-2-carboxylic acid[4-[4-(3-cyano-benzoyl)-piperazin-1-yl]-phenyl]-amide;

4′-Trifluoromethyl-biphenyl-2-carboxylic acid[4-(4-acetyl-piperazin-1-yl)-phenyl]-amide;

4′-Trifluoromethyl-biphenyl-2-carboxylic acid[4-[4-(3-cyano-benzenesulfonyl)-piperazin-1-yl]-phenyl]-amide;

4′-Trifluoromethyl-biphenyl-2-carboxylic acid[4-(4-methanesulfonyl-piperazin-1-yl)-phenyl]-amide;

4′-Trifluoromethyl-biphenyl-2-carboxylic acid[4-[1-(3-cyano-benzyl)-piperidin-4-yl]-phenyl]-amide;

N-{4-[4-(3-Cyano-benzyl)-piperazin-1-yl]-phenyl}-2-pyrrol-1-yl-benzamide;

N-{4-[4-(3-Cyano-benzyl)-piperazin-1-yl]-phenyl}-2-pyridin-2-yl-benzamide;

or a physiologically acceptable salt, solvate or derivative thereof.

Preferred compounds of the invention include:

4′-Trifluoromethyl-biphenyl-2-carboxylic acid[4-[4-(3-cyano-benzyl)-piperazin-1 -yl]-phenyl]-amide;

4′-Isopropyl-5-methyl-biphenyl-2-carboxylic acid[4-[4-(3-cyano-benzyl)-piperazin-1-yl]-phenyl]-amide;

4′-Isopropyl-6-methoxy-biphenyl-2-carboxylic acid[4-[4-(3-cyano-benzyl)-piperazin-1-yl]-phenyl]-amide;

4′-Isopropyl-6-methyl-biphenyl-2-carboxylic acid[4-[4-(3-cyano-benzyl)-piperazin-1-yl]-phenyl]-amide;

6-Methyl-4′-trifluoromethyl-biphenyl-2-carboxylic acid[4-[4-(3-cyano-benzyl)-piperazin-1-yl]-phenyl]-amide;

4′-Isopropyl-5-methyl-biphenyl-2-carboxylic acid(4-{3-(3-methyl-[1,2,4]oxadiazol-5-yl)-benzyl]-piperazin-1-yl}-phenyl)-amide;

4′-Trifluoromethyl-biphenyl-2-carboxylic acid[4-(4-carbamoylmethyl-piperazin-1-yl)-phenyl]-amide;

4′-Isopropyl-6-methoxy-biphenyl-2-carboxylic acid[4-(4-carbamoylmethyl-piperazin-1-yl)-phenyl]-amide;

4′-Isopropyl-6-methyl-biphenyl-2-carboxylic acid[4-(4-carbamoylmethyl-piperazin-1-yl)-phenyl]-amide;

4′-Isopropyl-6-methyl-biphenyl-2-carboxylic acid(4-(4-(3-(3-methyl-[1,2,4]oxadiazol-5-yl)-benzyl)-piperazine-1-yl)-phenyl)-amide;

4′-Trifluoromethyl-biphenyl-2-carboxylic acid[4-(4-(1H-pyrrol-2-ylmethyl)-piperazin-1-yl)-phenyl]-amide;

4′-Isopropyl-5-methyl-biphenyl-2-carboxylic acid[4-(4-(1H-pyrrol-2-ylmethyl)-piperazin-1-yl)-phenyl]-amide;

5-Methyl-4′-trifluoromethyl-biphenyl-2-carboxylic acid[4-(4-(1H-pyrrol-2-ylmethyl)-piperazin-1-yl)-phenyl]-amide;

or a physiologically acceptable salt, solvate or derivative thereof.

The term “physiologically functional derivative” as used herein refersto any physiologically acceptable derivative of a compound of thepresent invention, for example, an ester, which upon administration to amammal, such as a human, is capable of providing (directly orindirectly) such a compound or an active metabolite thereof. Suchderivatives are clear to those skilled in the art, without undueexperimentation, and with reference to the teaching of Burger′sMedicinal Chemistry And Drug Discovery, 5th Edition, Vol 1: PrinciplesAnd Practice, which is incorporated herein by reference.

The compounds of the invention are inhibitors of hepatic production ofapoB-100 and are thus of use in the treatment of conditions resultingfrom elevated circulating levels of apoB-100.

The ability of the compounds of the invention to inhibit the productionof apoB-100 by human hepatocytes in vitro is determined using primaryhuman hepatocytes as a model system. The specificity of the compounds ofthe invention is established by comparing the effects on apoB-100,apoprotein A-1, and fibrinogen production. A specificity of at least 100is preferred.

The in vivo profile of the compounds was determined by acute oraladministration of the compounds of the invention to DBN/2 mice andWistar rats with measurement of apoB-100 plasmatic levels as percentageof control values. Active compounds are further evaluated in Wistar ratsby repeated oral administration (once a day) with measurement of totalcholesterol, low density lipoprotein-cholesterol, triglycerides,apoB-100 and apoA-1 plasmatic levels as a percentage of control values.

The compounds of the invention are potent and specific inhibitors ofhepatic production of apoB-100, which furthermore exhibit good oralbioavailability and duration of action.

Compounds of the invention are of use in the treatment ofatherosclerosis, pancreatitis, non-insulin dependent diabetes mellitus(NIDDM), and coronary heart diseases.

Compounds of the invention are also useful in lowering serum lipidlevels, cholesterol and/or triglycerides, and are of use in thetreatment of hyperlipemia, hyperlipidemia, hyperlipoproteinemia,hypercholesterolemia and/or hypertriglyceridemia.

The invention therefore provides a compound of formula (I) or aphysiologically acceptable salt, solvate or derivative thereof for usein therapy, in particular in human medicine.

There is also provided as a further aspect of the invention the use of acompound of formula (I) or a physiologically acceptable salt, solvate orderivative thereof in the preparation of a medicament for use in thetreatment of conditions resulting from elevated circulating levels ofapoB-100.

In an alternative or further aspect there is provided a method for thetreatment of a mammal, including man, in particular in the treatment ofconditions resulting from elevated circulating levels of apoB-100,comprising administration of an effective amount of a compound offormula (I) or a physiologically acceptable salt, solvate or derivativethereof.

It will be appreciated that reference to treatment is intended toinclude prophylaxis as well as the alleviation of established symptoms.Compounds of formula (I) may be administered as the raw chemical but theactive ingredient is preferably presented as a pharmaceuticalformulation.

Accordingly, the invention also provides a pharmaceutical compositionwhich comprises at least one compound of formula (I) or aphysiologically acceptable salt, solvate or derivative thereof andformulated for administration by any convenient route. Such compositionsare preferably in a form adapted for use in medicine, in particularhuman medicine, and can conveniently be formulated in a conventionalmanner using one or more pharmaceutically acceptable carriers orexcipients.

Thus compounds of formula (i) may be formulated for oral, buccal,parenteral, transdermal, topical (including ophthalmic and nasal), depotor rectal administration or in a form suitable for administration byinhalation or insufflation (either through the mouth or nose).

For oral administration, the pharmaceutical compositions may take theform of, for example, tablets or capsules prepared by conventional meanswith pharmaceutically acceptable excipients such as binding agents (e.g.pregelatinised maize starch, polyvinylpyrrolidone or hydroxypropylmethylcellulose); fillers (e.g. lactose, microcrystalline cellulose orcalcium hydrogen phosphate); lubricants (e.g. magnesium stearate, talcor silica); disintegrants (e.g. potato starch or sodium starchglycollate); or wetting agents (e.g. sodium lauryl sulphate). Thetablets may be coated by methods well known in the art. Liquidpreparations for oral administration may take the form of, for example,solutions, syrups or suspensions, or they may be presented as a dryproduct for constitution with water or other suitable vehicle beforeuse. Such liquid preparations may be prepared by conventional means withpharmaceutically acceptable additives such as suspending agents (e.g.sorbitol syrup, cellulose derivatives or hydrogenated edible fats);emulsifylng agents (e.g. lecithin or acacia); non-aqueous vehicles (e.g.almond oil, oily esters, ethyl alcohol or fractionated vegetable oils);and preservatives (e.g. methyl or propyl p-hydroxybenzoates or sorbicacid). The preparations may also contain buffer salts, flavouring,colouring and sweetening agents as appropriate.

Preparations for oral administration may be suitably formulated to givecontrolled release of the active compound.

For buccal administration the composition may take the form of tabletsor lozenges formulated in conventional manner.

For transdermal administration the compounds according to the inventionmay be formulated as creams, gels, ointments or lotions or as atransdermal patch. Such compositions may for example be formulated withan aqueous or oily base with the addition of suitable thickening,gelling, emulsifylng, stabilising, dispersing, suspending, and/orcolouring agents.

The compounds of the invention may be formulated for parenteraladministration by bolus injection or continuous infusion. Formulationsfor injection may be presented in unit dosageform e.g. in ampoules or inmulti-dose containers, with an added preservative. The compositions maytake such forms as suspensions, solutions or emulsions in oily oraqueous vehicles, and may contain formulatory agents such as suspending,stabilising and/or dispersing agents. Alternatively, the activeingredient may be in powder form for constitution with a suitablevehicle, e.g. sterile pyrogen-free water, before use.

The compounds of the invention may be formulated for topicaladministration in the form of ointments, creams, gels, lotions,pessaries, aerosols or drops (e.g. eye, ear or nose drops). Ointmentsand creams may, for example, be formulated with an aqueous or oily basewith the addition of suitable thickening and/or gelling agents.Ointments for administration to the eye may be manufactured in a sterilemanner using sterilised components.

Lotions, may be formulated with an aqueous or oily base and will ingeneral also contain one or more emulsifylng agents, stabilising agents,dispersing agents, suspending agents, thickening agents, or colouringagents. Drops may be formulated with an aqueous or non aqueous base alsocomprising one or more dispersing agents, stabilising agents,solubilising agents or suspending agents. They may also contain apreservative.

The compounds of the invention may also be formulated in rectalcompositions such as suppositories or retention enemas, e.g. containingconventional suppository bases such as cocoa butter or other glycerides.

The compounds of the invention may also be formulated as depotpreparations. Such long acting formulations may be administered byimplantation (for example subcutaneously or intramuscularly) or byintramuscular injection. Thus, for example, the compounds of theinvention may be formulated with suitable polymeric or hydrophobicmaterials (for example as an emulsion in an acceptable oil) or ionexchange resins, or as sparingly soluble derivatives, for example, as asparingly soluble salt.

For intranasal administration, the compounds of the invention may beformulated as solutions for administration via a suitable metered orunit dose device or alternatively as a powder mix with a suitablecarrier for administration using a suitable delivery device.

The compositions may contain from 0.1% upwards, e.g. 0.1-99% of theactive material, depending on the method of administration. A proposeddose of the compounds of the invention is 0.25 mg/kg to about 125 mg/kgbodyweight per day e.g. 20 mg/kg to 100 mg/kg per day. It will beappreciated that it may be necessary to make routine variations to thedosage, depending on the age and condition of the patient and theprecise dosage will be ultimately at the discretion of the attendantphysician or veterinarian. The dosage will also depend on the route ofadministration and the particular compound selected.

The compounds of formula (I) may, if desired, be administered with oneor more therapeutic agents and formulated for administration by anyconvenient route in a conventional manner. Appropriate doses will bereadily appreciated by those skilled in the art. For example, thecompounds of formula (I) may be administered in combination with an HMGCoA reductase inhibitor.

A compound of formula (I), or a physiologically acceptable salt, solvateor derivative thereof, may be prepared by the general methods outlinedhereafter. In the following description, the groups X, Y, Z, R¹, R² andR³ are as previously defined for compounds of formula (I), unlessspecified otherwise.

According to a general process (A), a compound of formula (I) may beprepared by reacting a compound of formula (II) with a compound offormula R′—Z—X—L

where L represents a suitable halide leaving group, e.g. chloride, understandard displacement conditions, or where X is an oxo group, L mayadditonally represent a hydroxy group, the reaction being effected understandard acid and amine coupling conditions.

A compound of formula (II) may be prepared by reaction of a compound offormula (III) with a compound of formula (IV)

where L is defined above and P is a suitable amine protecting group,e.g. tert-butoxycarbonyl (Boc), under standard coupling conditions foran acid and amine coupling, followed by deprotection of the protectinggroup under suitable conditions, e.g. acidic removal of a Boc group.

A compound of formula (IV), where A represents N, may be prepared by thetwo step reaction of a compound of formula (V)

comprising incorporation of the protecting group P using standardmethodology followed by reduction of the nitro group, e.g. underhydrogenation conditions.

A compound of formula (IV), where A represents CH, may be prepared froma compound of formula (VI)

by reaction with a suitable a compound of formula H₂N—P′ where P′ is asuitable protecting group which is labile under hydrogenationconditions, such as a benzyl group, using a suitable coupling agent oragents such as tris(dibenzylidene acetone)dipalladium,2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (binap) and sodiumtert-butoxide in a suitable solvent such as toluene, followed by removalof the protecting group and reduction of the double bond underhydrogenation conditions.

According to a second method (B), compounds of formula (I) may beprepared by reaction of compounds of formula (III) and compounds offormula (VII)

where L is defined above, under standard coupling conditions.

Compounds of formula (VII) may be prepared by reaction of a compound offormula (V) With a compound of formula R¹—Z—X—L, where L is definedabove, followed by reduction of the nitro group under hydrogenation orreductive tin chloride conditions.

According to a third process (C), a compound of formula (I) where Y is—O—C₁₋₄alkylene- may be prepared by reaction of a compound of formula(VIII) with a compound of formula R²—C₁₋₄alkylene-L, where L is definedabove,

Compounds of formula (VIII) may be prepared according to the processoutlined in process B.

According to a fourth general process (D), a compound of formula (I),where at least part of X represents an alkylene link to the piperidineor piperazine-group, may be prepared by reacting a compound of formula(II) with a compound of formula (IX)

where X′ represents X minus a methylene group, under standard reductiveamination conditions, e.g. using sodium triacetoxyborohydride in asolvent such as dichloroethane.

According to a fifth process (E), a compound of formula (I) may beprepared from a different compound of formula (I), using standardtechniques well known in the art. For example, compounds of formula (I)where R¹ comprises a group containing an amide group may be preparedfrom the compound of formula (I) where the corresponding positioncomprises a carboxylic acid group, which in turn may be prepared fromthe compound of formula (I) where the corresponding position comprises acarboxylic ester group. Well known methods in the art may be employed tofacilitate the transformation of an ester to an acid and then to anamide.

A compound of formula (III), where Y is a direct link, R² is a phenyl oran aromatic heterocyclyl and L is a hydroxy group, may be preparedfirstly by coupling a boronic acid with a suitable leaving group,represented by a compound of formula (X) and a compound of formula (XI)

where R²′ represents phenyl or an aromatic heterocyclyl, PG represents aprotected carboxylic acid and A and D represent either the boronic acidor the suitable leaving group, such as triflate or bromide, followed bydeprotection of the protecting group under standard conditions, such asbase removal of an ester group. Where L represents a halide leavinggroup, the carboxylic acid product can be treated with a suitablereagent, such as thionyl chloride, to give the corresponding chlorideleaving group.

Where R¹ is a phenyl, substituted by an aromatic he terocyclyl, thearomatic heterocyclyl may be introduced by any well known methods in theart. For instance, where the substituent is a methyl substitutedoxadiazole, this may be formed by treatment of a suitable benzamidederivative with a suitable reagent, such as dimethylacetamidedimethylacetal at elevated temperature, followed by cyclisation of theintermediate compound with hydoxylamine.

The various general methods described above may be useful for theintroduction of the desired groups at any stage in the stepwiseformation of the required compound, and it will be appreciated thatthese general methods can be combined in different ways in suchmulti-stage processes. The sequence of the reactions in multi-stageprocesses should of course be chosen so that the reaction conditionsused do not affect groups in the molecule which are desired in the finalproduct.

Compounds of formula R¹—Z—X—L, (III), (V) and (VI), (IX), (X) and (XI)are known or may be prepared by standard methods well known in the artand/or herein described.

Physiologically acceptable salts may also be prepared from other salts,including other physiologically acceptable salts, of the compound offormula (I) using conventional methods.

The compounds of formula (I) may readily be isolated in association withsolvent molecules by crystallisatioq from or evaporation of anappropriate solvent to give the corresponding solvates.

When a specific enantiomer of a compound of general formula (I) isrequired, this may be obtained for example by resolution of acorresponding enantiomeric mixture of a compound of formula (I) usingconventional methods.

Thus, in one example an appropriate optically active acid may be used toform salts with the enantiomeric mixture of a compound of generalformula (I). The resulting mixture of isomeric salts may be separated,for example, by fractional crystallisation into the diastereoisomericsalts from which the required enantiomer of a compound of generalformula (I) may be isolated by conversion into the required free base.

Alternatively, enantiomers of a compound of general forrmula (I) may besynthesised from the appropriate optically active intermediates usingany of the general processes described herein.

The invention is further illustrated by the following intermediates andexamples. All temperatures are in degrees centigrade.

Abbreviations:

MS-LCMS mass spectrography, HOBt-1-Hydroxybenzotriazole, AcOEt-Ethylacetate, EDCl-1-(3-dimethylaminopropyl)-3-ethylcarbodiimidehydrochloride, BINAP-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl,THF-Tetrahydrofuran, MeOH-Methanol, EtOH-Ethanol, Et₃N-Triethylamine

INTERMEDIATE 1

5-Methoxy-4′-trifluoromethyl-biphenyl-2-carboxylic Acid Methyl Ester

To a stirred solution of4-methoxy-2-(trifluoro-methanesulfonyloxy)-benzoic acid methyl ester(6.28 g) in toluene (100 mL) was added LiCl (2.54 g) and Pd(PPh₃)₄ (1.15g). After few minutes at room temperature, a 2M solution of Na₂CO₃ (26mL) was added followed by a solution of 4-trifluoromethylphenyl boronicacid (4.17 g) in EtOH (30 mL). The resulting mixture was stirred underreflux for 6 hours. The mixture was cooled to room temperature and thephases were separated. The organic layer was then dried over Na₂SO₄,filtered and evaporated under reduced pressure. The residue was purifiedby flash chromatography eluting with hexane/AcOEt (90/10) to give thetitle compound (5.7 g) as white crystals.

m.p.: 93-94° C.

Simlilarly prepared were:

INTERMEDIATE 2

4′-Isopropyl-5-methyl-biphenyl-2-carboxylic acid methyl ester as an oil(10 g), GCMS: m/z 268 (M+) from4-methyl-2-(trifluoro-methanesulfonyloxy)-benzoic acid methyl ester(11.9 g) and 4-isopropylphenyl boronic acid (7.2 g).

INTERMEDIATE 3

5-Methyl-4′-trifluoromethyl-biphenyl-2-carboxylic acid methyl ester as apale yellow oil (4.2 g), GCMS: m/z 294(M+) from4-methyl-2-(trifluoro-methanesulfonyloxy)-benzoic acid methyl ester (4.7g) and 4-trifluoromethylphenyl boronic acid (3.3 g).

INTERMEDIATE 4

6-Methoxy-4′-trifluoromethyl-biphenyl-2-carboxylic acid methyl ester asan oil (6.8 g), GCMS: m/z 310 (M+) from3-methoxy-2-(trifluoro-methanesulfonyloxy)-benzoic acid methyl ester(8.6 g) and 4-trifluoromethylphenyl boronic acid (5 g).

INTERMEDIATE 5

4′-Isopropyl-6-methoxy-biphenyl-2-carboxylic acid methyl ester as an oil(10 g), GCMS: m/z 284 (M+) from3-methoxy-2-(trifluoro-methanesulfonyloxy)-benzoic acid methyl ester(12.2 g) and 4-isopropylphenyl boronic acid (7 g).

INTERMEDIATE 6

4′-Isopropyl-6-methyl-biphenyl-2-carboxylic acid methyl ester as acolorless oil (15.3 g), GCMS: m/z 268 (M+) from3-methyl-2-(trifluoro-methanesulfonyloxy)-benzoic acid methyl ester(15.7 g) and 4-isopropylphenyl boronic acid (10 g).

INTERMEDIATE 7

6-Methyl-4′-trifluoromethyl-biphenyl-2-carboxylic acid methyl ester as acolorless oil (13.7 g), GCMS: m/z 294 (M+) from3-methyl-2-(trifluoro-methanesulfonyloxy)-benzoic acid methyl ester(15.7 g) and 4-tnifluoromethylphenyl boronic acid (10 g).

INTERMEDIATE 8

2-(4′-Isopropyl-5-methoxy-biphenyl-2-yl)-4,4-dimethyl-4,5-dihydro-oxazole

To a suspension of magnesium (0.69 g) in Et₂O (5 mL) containing a traceof iodine was added dropwise a solution of 1-bromo4-isopropyl-benzene(5.97 g) in Et₂O (50 mL). Following the addition, the mixture was heatedunder reflux for 1 hour. The resulting grignard solution was thencarrefully added to a solution of2-(2,4-dimethoxy-phenyl)-4,4-dimethyl-4,5-dihydro-oxazole (3.52 g) inTHF (60 mL) and the mixture was stirred at room temperature for 16hours. The reaction mixture was then poured into saturated aqueoussolution of NH₄Cl and the mixture was extracted with Et₂O, dried overNa₂SO₄, filtered and evaporated under reduced pressure. The residue waspurified by flash chromatography eluting with CH₂Cl₂/AcOEt (85/15) togive the title compound (3.5 g) as a pale yellow oil.

MS: m/z 324 (M+1).

Similarly prepared was:

INTERMEDIATE 9

2-(5-Chloro-4′-isopropyl-biphenyl-2-yl)-4,4-dimethyl-4,5-dihydro-oxazoleas a yellow oil (7.5 g), MS: m/z 326 (M−1) from2-(4-chloro-2-methoxy-phenyl)-4,4imethyl-4,5-dihydro-oxazole (10.2 g)and 1-bromo4-isopropyl-benzene (17.3 g).

INTERMEDIATE 10

5′-Chloro-2′-methyl-4-trifluoromethyl-biphenyl

To a solution of 2-bromo-4-chloro-toluene (20.5 g) in toluene (100 mL)was added Pd(PPh₃)₄ (1 g) and the mixture was stirred at roomtemperature under N₂ for 0.25 hours. A 2M solution of Na₂CO₃ (100 mL)was then added, followed by the dropwise addition of4-trifluoromethylphenyl boronic acid (19 g) in MeOH (100 mL). Theresulting mixture was heated under reflux for 48 hours. The mixture wasthen cooled to room temperature and the phases were separated. Theorganic layer was then dried over Na₂SO₄, filtered and evaporated underreduced pressure. The residue was purified by flash chromatographyeluting with petroleum ether/AcOEt (90/10) to give the title compound(25.3 g) as a colorless liquid.

GCMS: m/z 270 (M+).

INTERMEDIATE 11

5-Methoxy-4′-trifluoromethyl-biphenyl-2-carboxylic Acid

5-Methoxy-4′-trifluoromethyl-biphenyl-2-carboxylic acid methyl ester(5.6 g) was placed in suspension in EtOH (80 mL) and a solution of NaOH(2.9 g) in water (40 mL) was added. The mixture was stirred under refluxfor 2 hours and EtOH was evaporated under reduced pressure. The aqueouslayer was then acidified with concentrated HCl and the resulting solidwhich formed was filtered, washed with water and dried to give the titlecompound (5.1 g) as white crystals. m.p.: 232-234° C.

Similarly prepared were:

INTERMEDIATE 12

4′-Isopropyl-5-methyl-biphenyl-2-carboxylic acid as white crystals (9g), m.p.: 109-111° C. from 4′-isopropyl-5-methyl-biphenyl-2-carboxylicacid methyl ester (10 g).

INTERMEDIATE 13

5-Methyl-4′-trifluoromethyl-biphenyl-2-carboxylic acid as white crystals(3.7 g), m.p.: 176-178° C. from5-methyl-4′-trifluoromethyl-biphenyl-2-carboxylic acid methyl ester (4.2g).

INTERMEDIATE 14

6-Methoxy-4′-trifluoromethyl-biphenyl-2-carboxylic acid as whitecrystals (2.5 g), m.p.: 207-209° C. from6-methoxy-4′-trifluoromethyl-biphenyl-2-carboxylic acid methyl ester(6.8 g).

INTERMEDIATE 15

4′-Isopropyl-6-methoxy-biphenyl-2-carboxylic acid as white crystals (8.4g), m.p.: 132-134° C. from 4′-isopropyl-6-methoxy-biphenyl-2-carboxylicacid methyl ester (10 g).

INTERMEDIATE 16

4′-Isopropyl-6-methyl-biphenyl-2-carboxylc acid as white crystals (10g), m.p.: 145-146° C. from 4′-isopropyl-6-methyl-biphenyl-2-carboxylicacid methyl ester (15.3 g).

INTERMEDIATE 17

6-Methyl-4′-trifluoromethyl-biphenyl-2-carboxylic acid as white crystals(8.5 g), m.p.: 206-208° C. from6-methyl-4′-trifluoromethyl-biphenyl-2-carboxylic acid methyl ester (10g).

INTERMEDIATE 18

4′-Isopropyl-5-methoxy-biphenyl-2-carboxylic Acid

A solution of2-(4′-isopropyl-5-methoxy-biphenyl-2-yl)-4,4-dimethyl-4,5-dihydro-oxazole(3.4 g) in 4.5N HCl (200 mL) was stirred under reflux for 48 hours. Themixture was then cooled to room temperature and was extracted with Et₂O.The organic phase was then washed with brine, dried over Na₂SO₄,filtered and evaporated under reduced pressure to give the titlecompound (2.5 g) as an off white solid.

m.p.: 188-190° C.

Similarly prepared was:

INTERMEDIATE 19

5-Chloro-4′-isbpropyl-biphenyl-2-carboxylic acid as white crystals (2.2g), m.p.: 145-147° C. from2-(5-chloro-4′-isopropyl-biphenyl-2-yl)-4,4-dimethyl-4,5-dihydro-oxazole(7.5 g).

INTERMEDIATE 20

5-Chloro-4′-trifluoromethyl-biphenyl-2-carboxylic Acid

To a solution of 5′-chloro-2′-methyl-4-trifluoromethyl-biphenyl (27 g)in a mixture of t-butanol (100 mL) and H₂O (200 mL) was addedportionwise KMnO₄ (46.9 g). At the end of the addition, the mixture washeated under reflux for 16 hours, cooled to room temperature andfiltered on celite. The filtrate was then acidified with concentratedHCl and the aqueous layer was extracted with AcOEt. The combined organicextracts were washed with brine, dried over Na₂SO₄, filtered andevaporated under reduced pressure to give the title compound (24 g) aswhite crystals.

m.p.: 174-176° C.

INTERMEDIATE 21

1-(3-Cyano-benzyl)-4-(4-nitro-phenyl)-piperazine

To a stirred solution of 1-(4-nitro-phenyl)-piperazine (35.9 g) andpotassium carbonate (71.6 g) in acetone (500 mL) was added dropwise3-cyano-benzyl bromide (34 g) at room temperature and the mixture washeated under reflux. After 4 hours, the salts were removed byfiltration, washed with acetone and the filtrate was evaporated todryness. The residue was taken in CH₂Cl₂ and the solution was washedwith water, dried over Na₂SO₄, filtered and evaporated. The oily residuewas crystallized from AcOEt/diisopropyl ether to give the title compound(52 g) as orange crystals.

m.p.: 120-122° C.

INTERMEDIATE 22

4-[4-(3-Cyano-benzyl)-piperazin-1-yl]-phenylamine

To a stirred solution of1-(3-cyano-benzyl)-4-(4-nitro-phenyl)-piperazine (52 g) in EtOH (1.2 L)and THF (300 mL) was added portionwise SnC₂.2H₂O (145.6 g) at roomtemperature and the mixture was heated at 55° C. for 16 hours. Afterevaporation of the solvents, the residue was taken in water, basifiedwith NaOH at pH 14 and extracted with CH₂Cl₂. The organic layer was thenwashed with water, dried over Na₂SO₄, and evaporated. The residue wascristallized from disopropyl ether to give the title compound (40.5 g)as pale yellow crystals.

m.p.: 99-101° C.

INTERMEDIATE 23

N-[4-[3-Cyano-benzyl)-piperazin-1-yl]-phenyl]-2-hydroxy-benzamide

To a stirred solution of4-[4-(3-cyano-benzyl)-piperazin-1-yl]-phenylamine (2.24 g),2-hydroxy-benzoic acid (1.08 g), HOBt (1.35 g), and Et3N (1 g) in CH₂Cl₂(70 mL) was added at room temperature EDCl (1.9 g) and the mixture wasstirred at room temperature for 4 hours. The organic solution was thenwashed with water, with a saturated solution of NaHCO₃, with brine anddried over Na₂SO₄. After filtration and evaporation of the filtrate, theresidue was purified by flash chromatography eluting with CH₂Cl₂/MeOH(98/2) to~give the title compound (1.85 g) as a yellow solid.

m.p.: 79-81° C.

Similarly prepared was:

INTERMEDIATE 24

N-[4-[3-Cyano-benzyl)-piperazin-1-yl]-phenyl]-2-hydroxy-3-methoxy-benzamideas pale yellow crystals (3.4 g), m.p.: 160-162° C. from4-[4-(3-cyano-benzyl)-piperazin-1-yl]-phenylamine (4.39 g) and2-hydroxy-3-methoxy-benzoic acid (2.56 g).

INTERMEDIATE 25

4-(4-Nitro-phenyl)-piperazine-1-carboxylic Acid tert-butyl Ester

To a solution of 1-(4-nitro-phenyl)-piperazine (15.5 g) in CH₂Cl₂ (250mL) was added Et₃N (8.3 g). The solution was cooled to 0° C. anddi-tert-butyl dicarbonate (17.1 g) was added portionwise. After 16 hoursat room temperature, the solution was washed with water, with asaturated solution of NaHCO₃ and brine. The organic phase was dried overNa₂SO₄, filtered and evaporated under reduced pressure and the resultingsolid was recrystallized from MeOH to give the title compound (21.5 g)as pale yellow crystals.

m.p.: 149-151° C.

INTERMEDIATE 26

4-(3-Nitro-phenyl)-piperazine-1-carboxylic Acid tert-butyl Ester

To a solution of 1-iodo-3-nitro-benzene (9 g), piperazine-1-carboxylicacid tert-butyl ester (13.5 g) and sodium tert-butoxide (9.7 g) indioxane (150 mL) was added tris(dibenzylideneacetone)dipalladium (2 g)and tri-o-tolylphosphine (2.2 g) and the mixture was heated at refluxfor 24 hours. The solution was then cooled to room temperature, taken inEt₂O and washed with brine. The organic layer was dried over Na₂SO₄,filtered and concentrated under reduced pressure. The crude residue wasrecrystallized from diisopropyl ether to give the title compound (6 g)as a yellow solid.

m.p.: 126-128° C.

INTERMEDIATE 27

4-(4-Amino-phenyl)-piperazine-1-carboxylic Acid tert-butyl Ester

A solution of 4-(4-nitro-phenyt)-piperazine-1-carboxylic acid tert-butylester (21.4 g) in EtOH (250 mL) containing Pd/C 10% (0.5 g) washydrogenated at room temperature. After 16 hours, the catalyst wasremoved by filtration and the filtrate was evaporated under reducedpressure. The oily residue was then crystallized from cyclohexane togive the title compound (17.8 g) as pink crystals.

m.p.: 95-96° C.

Similarly prepared was:

INTERMEDIATE 28

4-(3-Amino-phenyl)-piperazine-1-carboxylic acid tert-butyl ester as anoil (2.5 g), MS: m/z 278(M+1) from4-(3-nitro-phenyl)-piperazine-1-carboxylic acid tert-butyl ester (6 g).

INTERMEDIATE 29

4-{4-[(4′-Trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-piperazine-1-carboxylicAcid tert-butyl Ester

Method A:

To a stirred solution of 4-(4-amino-phenyl)-piperazine-1-carboxylic acidtert-butyl ester (1.38 g), 4′-trifluoromethyl-biphenyl-2-carboxylic acid(1.33 g), HOBt (0.81 g), and Et₃N (0.6 g) in CH₂Cl₂ (30 mL) was addedEDCl (1.15 g) and the mixture was stirred at room temperature for 6hours. The organic solution was then washed with water, with a saturatedsolution of NaHCO₃ and dried over Na₂SO₄. After filtration andevaporation of the filtrate, the residue was purified by flashchromatography eluting with CH₂Cl₂/AcOEt (90/10) and the resulting oilycompound was crystallized from EtOH to give the title compound (2.3 g)as white crystals.

m.p.: 214-215° C.

Method B:

To a stirred solution of 4-(4-amino-phenyl)-piperazine-1-carboxylic acidtert-butyl ester (8.1 g) in CH₂Cl₂ (150 mL) was added Et₃N (3.33 g) andthe mixture was cooled at 0° C. To this solution was added dropwise4′-trifluoromethyl-biphenyl-2-carbonyl chloride (8.53 g) in CH₂Cl₂ (80mL) and the mixture was stirred at room temperature for 1 hour. Theorganic solution was then sequentially washed with water, with asaturated solution of NaHCO₃, with brine, then dried over Na₂SO₄,filtered and evaporated. The oily residue by trituration fromdiisopropyl ether give the title compound (13.6 g) as white crystals.

m.p.: 213-215° C.

INTERMEDIATE 30

4-{4-[(4′-Isopropyl-5-methyl-biphenyl-2-carbonyl)-amino]-phenyl}-piperazine-1-carboxylicAcid tert-butyl Ester

To a stirred solution of 4-(4-amino-phenyl)-piperazine-1-carboxylic acidtert-butyl ester (4.15 g), 4′-isopropyl-5-methyl-biphenyl-2-carboxylicacid (3.81 g), HOBt (2.36 g), and Et₃N (1.97 g) in CH₂Cl₂ (50 mL) wasadded EDCl (3.72 g) and the mixture was stirred at room temperature for16 hours. The organic solution was then washed with water, with asaturated solution of NaHCO₃, with brine and dried over Na₂SO₄. Afterfiltration and evaporation of the filtrate, the residue was crystallizedfrom diisopropyl ether to give the title compound (4 g) as whitecrystals.

m.p.: 173-175° C.

Similarly prepared were:

INTERMEDIATE 31

4-{4-[(4′-Isopropyl-6-methoxy-biphenyl-2-carbonyl)-amino]-phenyl}-piperazine-1-carboxylicacid tert-butyl ester as white crystals (1.9 g),

m.p.:, 155-157° C. from 4′-isopropyl-6-methoxy-biphenyl-2-carboxylicacid (1.94 g) and 4-(4-amino-phenyl)-piperazine-1-carboxylic acidtert-butyl ester (2 g).

INTERMEDIATE 32

4-{4-[(6-Methyl-4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-piperazine-1-carboxylicacid tert-butyl ester as white crystals (1.5 g), m.p.: 163-165° C. from6-methyl-4′-trifluoromethyl-biphenyl-2-carboxylic acid (2 g) and4-(4-amino-phenyl)-piperazine-1-carboxylic acid tert-butyl ester (2 g).

INTERMEDIATE 33

4-{4-[(4′-Isopropyl-6-methyl-biphenyl-2-carbonyl)-amino]-phenyl}-piperazine-1-carboxylicacid tert-butyl ester as white crystals (1.8 g), m.p.: 140-142° C. from4′-isopropyl-6-methyl-biphenyl-2-carboxylic acid (1.83 g) and4-(4-amino-phenyl)-piperazine-1-carboxylic acid tert-butyl ester (2 g).

INTERMEDIATE 34

4-{4-[2-(4-Fluoro-benzyloxy)-benzoylamino]-phenyl}-piperazine-1-carboxylicacid tert-butyl ester as white crystals (6.7 g), m.p.: 170-171° C. from4-(4-amino-phenyl)-piperazine-1-carboxylic acid tert-butyl ester (4.15g) and 2-(4-fluoro-benzyloxy)-benzoic acid (3.69 g).

INTERMEDIATE 35

4-{3-[(4′-Trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-piperazine-1-carboxylicacid tert-butyl ester as a white solid (3.3 g), m.p.: 160° C. from4-(3-amino-phenyl)-piperazine-1-carboxylic acid tert-butyl ester (2.5 g)and 4′-tnfluoromethyl-biphenyl-2-carboxylic acid (2.5 g).

INTERMEDIATE 36

4′-Trifluoromethyl-biphenyl-2-carboxylic Acid(4-piperazin-1-yl-phenyl)-amide

To a solution of4-{4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino)-phenyl}-piperazine-1-carboxylicacid tert-butyl ester (11.7 g) in CH₂Cl₂ (50 mL) was addedtrifluoroacetic acid (25 mL) and the solution was stirred at roomtemperature for 2 hours. The mixture was then evaporated under reducedpressure and the residue was taken in water. The resulting precipitatewas filtered and washed with water. The resulting solid was thensuspended in water, basified with a saturated solution of Na₂CO₃, andextracted with CH₂Cl₂. The organic phase was then washed with water,dried over Na₂SO₄, filtered and evaporated to give the title compound (9g) as white crystals.

m.p.: 119-124° C.

INTERMEDIATE 37

4′-Isopropyl-5-methyl-biphenyl-2-carboxylic Acid(4-piperazin-1-yl-phenyl)-amide

To a solution of4-{4-[(4′-isopropyl-5-methyl-biphenyl-2-carbonyl)-amino]-phenyl}-piperazine-1-carboxylicacid tert-butyl ester (4 g) in CH₂Cl₂ (20 mL) was added trifluoroaceticacid (15 mL) and the solution was stirred at room temperature for 16hours. The mixture was then evaporated under reduced pressure and theresidue was taken in water and basified with a 1N NaOH aqueous solution.The resulting precipitate was extracted with CH₂Cl₂ and the organicphase was washed with water, dried over Na₂SO₄ filtered and evaporatedto give the title compound (3 g) as white crystals.

m.p.: 131-133° C.

Similarly prepared were

INTERMEDIATE 38

4′-Isopropyl-6-methoxy-biphenyl-2-carboxylic acid(4-piperazin-1-yl-phenyl)-amide as white crystals (1.3 g), m.p.:157-159° C. from4-{4-[(4′-isopropyl-6-methoxy-biphenyl-2-carbonyl)-amino]-phenyl}-piperazine-1-carboxylicacid tert-butyl ester (1.9 g).

INTERMEDIATE 39

6-Methyl-4′-trifluoromethyl-biphenyl-2-carboxylic acid(4-piperazin-1-yl-phenyl)-amide as white crystals (0.9 g), m.p.:155-157° C. from4-{4-[(6-methyl-4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-piperazine-1-carboxylicacid tert-butyl ester (1.5 g).

INTERMEDIATE 40

4′-Isopropyl-6-methyl-biphenyl-2-carboxylic acid(4-piperazin-1-yl-phenyl)-amide as white crystals (1.2 g), m.p.: 130° C.from4-{4-[(4′-isopropyl-6-methyl-biphenyl-2-carbonyl)-amino]-phenyl}-piperazine-1-carboxylicacid tert-butyl ester (1.8 g).

INTERMEDIATE 41

2-(4-Fluoro-benzyloxy)-N-(4-piperazin-1-yl-phenyl)-benzamide as whitecrystals (3.6 g), m.p.: 143-146° C. from4-{4-[2-(4-fluoro-benzyloxy)-benzoylamino]-phenyl}-piperazine-1-carboxylicacid tert-butyl ester (6 g).

INTERMEDIATE 42

4′-Trifluoromethyl-biphenyl-2-carboxylic acid(3-piperazin-1-yl-phenyl)-amide as white crystals (2.5 g), m.p.:101-103° C. from4-{3-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-piperazine-1-carboxylicacid tert-butyl ester (3.3 g).

INTERMEDIATE 43

4-(4-Bromo-phenyl)-3,6-dihydro-2H-pyridine-1-carboxylic Acid tert-butylEster

To a solution of 4-(4-bromo-phenyl)-1,2,3,6-tetrahydro-pyridine (2.39 g)in CH₂Cl₂ (30 mL) was added Et₃N (2 g). The solution was cooled at 0° C.and di-tert-butyl dicarbonate (2.29 g) was added. After 16 hours at roomtemperature, the solution was washed with water, with a saturatedsolution of NaHCO₃ and brine. The organic phase was dried over Na₂SO₄,filtered and evaporated under reduced pressure and the residue waspurified by flash chromatography eluting with CH₂Cl₂ to give the titlecompound (2 g) as a white solid.

m.p.: 68-70° C.

INTERMEDIATE 44

4-(4-Benzylamino-phenyl)-3,6-dihydro-2H-pyridine-1-carboxylic Acidtert-butyl Ester

To a solution of 4-(4-bromo-phenyl)-3,6-dihydro-2H-pyridine-1-carboxylicacid tert-butyl ester (0.34 g), benzylamine (0.12 g) and sodiumtert-butoxide (0.13 g) in toluene (8 mL) were added tris(dibenzylideneacetone)dipalladium (2.2 mg) and Binap (4.6 mg) and the mixture washeated at 80° C. for 16 hours. The solution was then cooled to roomtemperature, filtered and the filtrate was evaporated under reducedpressure. The residue was purified by flash chromatography eluting withpetroleum ether/AcOEt (90/10) and the oily residue was crystallized fromdiisopropyl ether to give the title compound (0.27 g) as white crystals.

m.p.: 120-121° C.

INTERMEDIATE 45

4-(4-Aminophenyl)-piperidine-1-carboxylic Acid tert-butyl Ester

A solution of4-(4-benzylamino-phenyl)-3,6-dihydro-2H-pyridine-1-carboxylic acidtert-butyl ester (0.27 g) in EtOH (10 mL) containing Pd/C 10% (50 mg)was hydrogenated at room temperature. After 1 hour, the catalyst wasremoved by filtration and the filtrate was evaporated under reducedpressure to give the title compound (0.18 g) as a pale pink oil.

MS: m/z 277(M+1).

INTERMEDIATE 46

4-{4-[(4′-Trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-piperidine-1-carboxylicAcid tert-butyl Ester

To a stirred solution of 4-(4-aminophenyl)-piperidine-1-carboxylic acidtert-butyl ester (0.18 g), 4′-trifluoromethyl-biphenyl-2-carboxylic acid(0.17 g), HOBt (0.1 g), and Et₃N (80 mg) in CH₂Cl₂ (10 mL) was added atroom temperature EDCl (0.15 g) and the mixture was stirred at roomtemperature for 16 hours. The organic solution was then washed withwater, with a saturated solution of NaHCO₃ and dried over Na₂SO₄. Afterfiltration and evaporation of the filtrate, the residue was purified byflash chromatography eluting with petroleum ether/AcOEt (70/30) to givethe title compound (0.25 g) as an orange oil.

MS: m/z 523(M−1).

INTERMEDIATE 47

4′-Trifluoromethyl-biphenyl-2-carboxylic Acid(4-piperidin-4-yl-phenyl)-amide as Trifluoroacetate Salt

To a solution of4-{4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-piperidine-1-carboxylicacid tert-butyl ester (0.22 g) in CH₂Cl₂ (5 mL) was addedtrifluoroacetic acid (1 mL) and the solution was stirred at roomtemperature for 1 hour. The mixture was evaporated under reducedpressure and the residue taken in water. The resulting precipitate wasfiltered, washed with water and dried to give the title compound (0.23g) as white crystals.

m.p.: 223-225° C.

INTERMEDIATE 48

3-[1,3]Dioxolan-2-yl-benzamide

To a solution of 3-(1,3-dioxolan-2-yl)-benzonitrile (5.86 g) in amixture of EtOH (140 mL) and H₂O (60 mL) was added sodium hydroxide(6.46 g) and the mixture was heated under reflux for 2 hours. Thesolvent was evaporated under reduced pressure and the aqueous layer wasextracted with CH₂Cl₂. The organic phase was washed with water, driedover Na₂SO₄, filtered and evaporated to give the title compound (4.5 g)as a white solid.

m.p.: 92-94° C.

INTERMEDIATE 49

3-(3-Methyl-[1,2,4]oxadiazol-5-yl)-benzaldehyde

A mixture of 3-[1,3]dioxolan-2-yl-benzamide (2.3 g) anddimethylacetamide dimethylacetal (4 g) was heated under reflux for 1hour and then evaporated to dryness. The oily residue was dissolved indioxane (20 mL) and hydroxylamine hydrochloride (1.18 g), acetic acid(20 mL) and a 2N aqueous sodium hydroxide solution (9 mL) were added andthe mixture was heated at 90° C. for 2 hours. After evaporation, theresidue was dissolved in toluene (100 mL) and a 1N hydrochloric acidsolution (50 mL) was added and the mixture was stirred at reflux for 2hours. After cooling at room temperature the organic phase was decanted,washed with water, dried over Na₂SO₄, filtered and evaporated to givethe title compound (2.3 g) as a white solid.

m.p.: 114-116° C.

INTERMEDIATE 50

[4-(4-Benzyl-piperazine-1-yl)-phenyl]-carbamic Acid tert-butyl Ester

To a solution of 4-(4-benzyl-piperazine-1-yl)-phenylamine (32 g) inCH₂Cl₂ (500 mL) containing Et₃N (18.4 mL) was added dropwisedi-tert-butyl dicarbonate (28.8 g) at 0° C. After 20 hours at roomtemperature, the solution was washed with water, with a saturatedsolution of NaHCO₃ and brine. The organic phase was dried over Na₂SO₄,filtered and evaporated under reduced pressure to give the titlecompound (43.5 g) as a solid.

GCMS: m/z 367 (M+).

INTERMEDIATE 51

(4-Piperazin-1-yl-phenyl)-carbamic Acid tert-butyl Ester

A solution of [4-(4-benzyl-piperazine-1-yl)-phenyl)-carbamic acidtert-butyl ester (43.5 g) in EtOH (1 L) containing Pd/C 10% (4 g) washydrogenated at room temperature. After 72 hours, the catalyst wasremoved by filtration and the filtrate was evaporated under reducedpressure. The oily residue was then purified by flash chromatographyeluting with AcOEt/isopropylamine (90/10) and the solid obtained wasrecristallized from AcOEt to give the title compound (17.5 g) as whitecrystals.

m.p.: 155-157° C.

INTERMEDIATE 52

(4-{4-[3-(3-Methyl-[1,2,4]oxadiazo)-5-yl)-benzyl]-piperazin-1-yl}-phenyl)-carbamicAcid tert-butyl Ester

To a solution of (4-piperazin-1-yl-phenyl)-carbamic acid tertbutyl ester(2 g) in 1,2-dichloroethane (80 mL) was added3-(3-methyl-[1,2,4]oxadiazol-5-yl)-benzaldehyde (1.4 g) and acetic acid(0.67 g). The solution was cooled at 0° C. and sodium triacetoxyborohydride (3.15 g) was added portionwise and the mixture was stirredat room temperature for 16 hours. The solution was then washed with asaturated solution of NaHCO₃, with brine, dried over Na₂SO₄, filteredand evaporated under reduced pressure. The residue was purified by flashchromatography eluting with CH₂Cl₂/MeOH (98/2) to give the titlecompound (2.5 g) as a white solid.

m.p.: 159-161° C.

INTERMEDIATE 53

4-{4-[3-(3-Methyl-[1,2,4]oxadiazol-5-yl)-benzyl-1-piperazin-1-yl}-phenylamine

To a stirred solution of(4-{4-[3-(3-methyl-[1,2,4]oxadiazol-5-yl)-benzyl]-piperazin-1-yl}-phenyl)-carbamicacid tert-butyl ester (2.5 g) in CH₂Cl₂ (4 mL) was added trifluoroaceticacid (6 mL) and the mixture was stirred at room temperature for 16hours. After evaporation under reduced pressure, the residue was takenin water, basified with a 1N NaOH aqueous solution and extracted withCH₂Cl₂. The organic phase was then washed with water, dried over Na₂SO₄,filtered and evaporated. The oily residue was crystallized from MeOH/H₂Oto give the title compound (1.35 g) as a solid.

m.p.: 106-108° C.

INTERMEDIATE 54

3-(5-Trifluoromethyl-[1,2,4]oxadiazol-3-yl)-benzaldehyde

To a stirred solution of 3-(1,3-dioxolan-2-yl)-benzonitrile (4 g) inEtOH (130 mL) was added hydroxylamine hydrochloride (7.9 g) andpotassium carbonate (15.7 g) and the mixture was refluxed for 4 hours.The hot mixture was filtered and the remaining solids were washed withEtOH and the filtrate was evaporated under reduced pressure.The crudeamidoxime (4.2 g) was dissolved in trifluoroacetic acid (20 mL) and Et₃N(2 g) was added and the mixture was stirred at room temperature for 3hours. The solution was evaporated to dryness and the residue wasextracted with CH₂Cl₂. The organic phase was washed with water, driedover Na₂SO₄, filtered and evaporated. The residue was then dissolved intoluene (100 mL) and 1N aqueous hydrochloric acid (30 mL) was added andthe mixture was heated at reflux for 1 hour. The mixture was cooled toroom temperature, the organic phase was decanted and washed with brine,dried over Na₂SO₄, filtered and evaporated. The residue was purified byflash chromatography eluting with CH₂Cl₂ to give the title compound (2g) as a pale yellow oil.

GCMS: m/z 242 (M⁺).

EXAMPLE 1

4′-Trifluoromethyl-biphenyl-2-carboxylic Acid[4-[4-(3-cyano-benzyl)-piperazin-1-yl]-phenyl]-amide (Method 1)

To a stirred solution of4-[4-(3-cyano-benzyl)-piperazin-1-yl]-phenylamine (0.29 g),4′-trifluoromethyl-biphenyl-2-carboxylic acid (0.26 g), HOBt (0.16 g),and Et₃N (0.12 g) in CH₂Cl₂ (15 mL) was added at room temperature EDCl(0.23 g) and the mixture was stirred at room temperature for 4 hours.The organic solution was then washed with water, with a saturatedsolution of NaHCO₃ and dried over Na₂SO₄. After filtration andevaporation of the filtrate, the residue was purified by flashchromatography eluting with CH₂Cl₂/AcOEt (90/10) and the solid obtainedwas recrystallized from EtOH to give the title compound (0.48 g) aswhite crystals.

m.p.: 149-150° C.

Analysis for C32H27F3N4O Calculated: C,71.10; H,5.03; N,10.36; Found:C,_(70.82); H,5.35; N,10.19%.

EXAMPLE 2

4′-Isopropyl-5-methyl-biphenyl-2-carboxylic Acid[4-[4-(3-cyano-benzyl)-piperazin-1-yl]-phenyl]-amide

To a stirred solution of4-[4-(3-cyano-benzyl)-piperazin-1-yl]-phenylamine (150 mg),4′-isopropyl-5-methyl-biphenyl-2-carboxylic acid (127 mg), HOBt (87 mg),and Et₃N (64 mg) in CH₂Cl₂ (10 mL) was added at room temperature EDCl(124 mg) and the mixture was stirred at room temperature for 16 hours.The organic solution was then washed with water, with a saturatedsolution of NaHCO₃ and dried over Na₂SO₄. After filtration andevaporation of the filtrate, the oily residue was crystallized from EtOHto give the title compound (160 mg) as white crystals.

m.p.: 167-169° C.

Analysis for C35H36N4O Calculated: C,79.51; H,6.86; N,10.60; Found:C,79.41; H,6.61; N,10.81%.

EXAMPLE 3

4′-Isopropyl-6-methoxy-biphenyl-2-carboxylic Acid[4-[4-(3-cyano-benzyl)-piperazin-1-yl]-phenyl]-amide

To a stirred solution of4-[4-(3-cyano-benzyl)-piperazin-1-yl]-phenylamine (400 mg),4′-isopropyl-6-methoxy-biphenyl-2-carboxylic acid (444 mg), HOBt (222mg), and Et₃N (166 mg) in CH₂Cl₂ (20 mL) was added at room temperatureEDCl (315 mg) and the mixture was stirred at room temperature for 16hours. The organic solution was then washed with water, with a saturatedsolution of NaHCO₃ and dried over Na₂SO₄. After filtration andevaporation of the filtrate, the residue was purified by flashchromatography eluting with CH₂Cl₂/MeOH (95/5) to give the titlecompound (279 mg) as white crystals.

m.p.: 179° C.

Analysis for C35H36N4O2(0.5H₂O) Calculated: C,75.92; H,6.73; N,10.12;Found: C,75.65; H,6.48; N,10.35%.

EXAMPLE 4

4′-Isopropyl-6-methyl-biphenyl-2-carboxylic Acid[4-[4-(3-cyano-benzyl)-piperazin-1-yl]-phenyl-amide

To a stirred solution of4-[4-(3-cyano-benzyl)-piperazin-1-yl]-phenylamine (400 mg),4′-isopropyl-6-methyl-biphenyl-2-carboxylic acid (418 mg), HOBt (222mg), and Et₃N (166 mg) in CH₂Cl₂ (20 mL) was added at room temperatureEDCl (315 mg) and the mixture was stirred at room temperature for 16hours. The organic solution was then washed with water, with a saturatedsolution of NaHCO₃ and dried over Na₂SO₄. After filtration andevaporation of the filtrate, the residue was purified by flashchromatography eluting with CH₂Cl₂/MeOH (98/2) and crystallized fromAcOEt to give the title compound (304 mg) as white crystals.

m.p.: 137° C.

Analysis for C35H36N4O Calculated: C,79.51; H,6.86; N,10.60; Found:C,79.31; H,6.36; N,10.78%.

EXAMPLE 5

6-Methyl-4′-trifluoromethyl-biphenyl-2-carboxylic Acid[4-[4-(3-cyano-benzyl)-piperazin-1-yl]-phenyl]-amide

To a stirred solution of4-[4-(3-cyano-benzyl)-piperazin-1-yl]-phenylamine (400 mg),6-methyl-4′-trifluoromethyl-biphenyl-2-carboxylic acid (460 mg), HOBt(222 mg), and Et₃N (166 mg) in CH₂Cl₂ (20 mL) was added at roomtemperature EDCl (315 mg) and the mixture was stirred at roomtemperature for 16 hours. The organic solution was then washed withwater, with a saturated solution of NaHCO₃ and dried over Na₂SO₄. Afterfiltration and evaporation of the filtrate, the residue was purified byflash chromatography eluting with CH₂Cl₂/MeOH (98/2) and crystallizedfrom AcOEt to give the title compound (122 mg) as white crystals.

m.p.: 192° C.

Analysis for C33H29F3N4O Calculated: C,71.47; H,5.27; N,10.10; FoundC,71.32; H,5.23; N,10.17%.

EXAMPLE 6

4′-Isopropyl-5-methyl-biphenyl-2-carboxylic Acid(4-{3-(3-methyl-[1,2,4]oxadiazol-5-yl)-benzyl]-piperazin-1-yl}-phenyl)-amide

To a stirred solution of(4-{4-[3-(3-methyl-[1,2,4]oxadiazol-5-yl)-benzyl]-piperazin-1-yl}phenylamine(175 mg), 4′-isopropyl-5-methyl-biphenyl-2-carboxylic acid (127 mg),HOBt (87 mg), and Et₃N (67 mg) in CH₂Cl₂ (20 mL) was added at roomtemperature EDCl (124 mg) and the mixture was stirred at roomtemperature for 16 hours. The organic solution was then washed withwater, with a saturated solution of NaHCO₃ and dried over Na₂SO₄. Afterfiltration and evaporation of the filtrate, the residue was purified byflash chromatography eluting with CH₂Cl₂/MeOH (98/2) and crystallizedfrom CH₂Cl₂/diisproyl ether to give the title compound (110 mg) as whitecrystals.

m.p.: 145-147° C.

Analysis for C37H39N5O2 Calculated: C,75.87; H,6.71; N,11.96; Found:C,75.79; H,7.02; N,11.81%.

Similarly prepared were:

EXAMPLE 7

5-Chloro-4′-isopropyl-biphenyl-2-carboxylic acid[4-[4-(3-cyano-benzyl)-piperazin-1-yl]-phenyl]-amide as white crystals(280 mg), m.p.: 188-190° C. from5-chloro-4′-isopropyl-biphenyl-2-carboxylic acid (274 mg) and4-[4-(3-cyano-benzyl)-piperazin-1-yl]-phenylamine (292 mg).

Analysis for C34H33ClN4O Calculated: C,74.37; H,6.06; N,10.20; Found:C,74.56; H,6.20; N,10.05%.

EXAMPLE 8

6-Methoxy-4′-trifluoromethyl-biphenyl-2-carboxylic acid[4-[4-(3-cyano-benzyl)-piperazin-1-yl]-phenyl]-amide as white crystals(225 mg), m.p.: 215-217° C. from6-methoxy-4′-trifluoromethyl-biphenyl-2-carboxylic acid (150 mg) and4-[4-(3-cyano-benzyl)-piperazin-1-yl]-phenylamine (150 mg).

Analysis for C33H29F3N4O2 (0.4H₂O) Calculated: C,68.60; H,5.20; N,9.70;Found C,68.50; H,5.19; N,9.56%.

EXAMPLE 9

5-Methyl-4′-trifluoromethyl-biphenyl-2-carboxylic acid[4-[4-(3-cyano-benzyl)-piperazin-1-yl]-phenyl]-amide as white crystals(240 mg), m.p.: 166-168° C. from5-methyl-4′-trifluoromethyl-biphenyl-2-carboxylic acid (210 mg) and4-[4-(3-cyano-benzyl)-piperazin-1-yl]-phenylamine (219 mg).

Analysis for C33H29F3N4O Calculated: C,71.47; H,5.27; N,10.10; Found:C,71.89; H,5.72; N,10.18%.

EXAMPLE 10

5-Chloro-4′-trifluoromethyl-biphenyl-2-carboxylic acid[4-[4-(3-cyano-benzyl)-piperazin-1-yl]-phenyl]-amide as white crystals(0.25 g), m.p.: 164-165° C. from5-chloro-4′-trifluoromethyl-biphenyl-2-carboxylic acid (0.19 g) and4-[4-(3-cyano-benzyl)-piperazin-1-yl]-phenylamine (0.18 g).

Analysis for C32H26ClF3N4O(0.5 H2O) Calculated: C,65.81; H,4.66; N,9.59;Found: C,65.49; H,4.79; N,9.75%.

Similarly prepared were:

Molecular formula: CHN calc: CHN found: Example —Y—R² R³ or mass specm/z m.p. ° C. Ex 11 Ph H C31H28N4O(1.2 H₂O) 169-171 C, 75.34; H, 6.20;N, 11.34; C, 75.07; H, 5.97; N, 11.24%. Ex 12 Ph 5-OMe C32H30N4O2159-161 C, 76.47; H, 6.02; N, 11.15; C, 76.71; H, 5.90; N, 10.95%. Ex 13

4-Cl C32H26ClF3N4O C, 66.84; H, 4.56; N, 9.74; C, 66.31; H, 4.68; N,9.75%. 143-145 Ex 14

H C31H28N4O2(0.5 H₂O) C, 74.83; H, 5.87; N, 11.26; C, 74.59; H, 5.68; N,11.63%. 133-134 Ex 15

H C34H29N5O2(0.5 H₂O) C, 74.43; H, 5.51; N, 12.76; C, 74.07; H, 5.36; N,12.70%. 209-211 Ex 16

H 515(M + 1) 133-135 Ex 17

5-OMe 571(M + 1) 160-164 Ex 18

4-Me 555(M + 1) 120-124 Ex 19

4-OMe 571(M + 1) 151-155 Ex 20

H 501(M + 1) 118-122 Ex 21

H 503(M + 1) 124-128 Ex 22

H 541(M + 1) 117-121 Ex 23

H 491(M + 1) 200-202 Ex 24

H 501(M + 1) 140-144 Ex 25

H 501(M + 1) 72-76 Ex 26

H 533(M + 1) 116-120

EXAMPLE 27

N-[4-[4-(3-Cyano-benzyl)-piperazin-1-yl]-phenyl]-2-(4-trifluoromethyl-benzyloxy)-benzamide

To a stirred suspension ofN-[4-[3-cyano-benzyl)-piperazin-1-yl]-phenyl]-2-hydroxy-benzamide (0.309g) and K₂CO₃ (0.135 g) in acetone (10 mL) was added dropwise4-trifluoromethyl-benzyf chloride (0.14 g) and the mixture was heated atreflux. After 16 hours, the mixture was cooled at room temperature, thesalts were removed by filtration, washed with acetone and the filtratewas evaporated under reduced presssure. The residue was then purified byflash chromatography eluting with CH₂Cl₂/AcOEt (85/15) and the whitesolid obtained was recrystallized from EtOH to give the title compound(0.31 g) as white crystals.

m.p.: 190-191° C.

Analysis for C33H29F3N4O2 Calculated: C,69.46; H,5.12; N,9.82; FoundC,69.49; H,5.03; N,9.80%.

EXAMPLE 28

N-[4-[4-(3-Cyano-benzyl)-piperazin-1-yl]-phenyl]-3-methoxy-2-(4-trifluoromethyl-benzyloxy)-benzamide

To a stirred suspension ofN-[4-[3-cyano-benzyl)-piperazin-1-yl]-phenyl]-2-hydroxy-3-methoxy-benzamide(0.33 g) and K₂CO₃ (0.134 g) in acetone (15 mL) was added dropwise4-trifluoromethyl-benzyl chloride (0.146 g) and the mixture was heatedat reflux. After 16 hours, the mixture was cooled to room temperature,the salts were removed by filtration, washed with acetone and thefiltrate was evaporated under reduced presssure. The residue was thencrystallized from EtOH to give the title compound (0.29 g) as paleyellow crystals.

m.p.: 118-119.5° C.

Analysis for C34H31F3N4O3 Calculated: C,67.99; H,5.20; N,9.33; FoundC,67.98; H,5.07; N,9.32%.

Similarly prepared were

Molecular formula: CHN calc: Example Y—R² R³ CHN found: m.p. ° C. Ex 29

3-OMe C33H31FN4O3 C, 71.98; H, 5.67; N, 10.18; C, 72.50: H, 5.68; N,10.06%. 118-120 Ex 30

3-OMe C34H34N4O3 C, 74.70; H, 6.27; N, 10.25; C, 74.73; H, 6.37; N,10.10%. 140-142 Ex 31

3-OMe C34H40N4O3 C, 73.88; H, 7.29; N, 10.14; C, 74.30; H, 6.91; N,9.97%. 102-104 Ex 32

H C33H38N4O2 C, 75.83; H, 7.33; N, 10.72; C, 76.34; H, 7.19; N, 10.52%.119-121 Ex 33

3-OMe C35H36N4O3 C, 74.98; H, 6.47; N, 9.99; C, 74.57; H, 6.42; N,9.70%. 134-136

EXAMPLE 34

4′-Trifluoromethyl-biphenyl-2-carboxylic Acid[4-[4-(3-cyano-benzyl)-piperazin-1-yl]-phenyl]-amide-(Method 2)

To a solution of 4′-trifluoromethyl-biphenyl-2-carboxylic acid(4-piperazin-1-yl-phenyl)-amide (0.58 g) in CH₂Cl₂ (35 mL) containingEt₃N (0.152 g) was added 3-cyano-benzyl bromide (0.267 g) and themixture was heated at reflux for 2 hours. The solution was washed withwater, dried over Na₂SO₄, filtered and evaporated. The residue waspurified by′ flash chromatography eluting with CH₂Cl₂/MeOH (98/2) andthe solid obtained was recrystallized from MeOH/H₂O to give the titlecompound (0.67 g) as white crystals.

m.p.: 153-155° C.

Analysis for C32H27F3N4O Calculated: C,71.10; H,5.03 N,10.36; Found:C,70.86; H,4.98; N,10.27%.

EXAMPLE 35

N-4-[4-(3-Cyano-benzyl)-piperazin-1-yl]-phenyl]-2-(4-fluoro-benzyloxy)-benzamide

To a solution of2-(4-fluoro-benzyloxy)-N-(4-piperazin-1-yl-phenyl)-benzamide (0.31 g) inCH₂Cl₂ (10 mL) containing Et₃N (84 mg) was added 3-cyano-benzyl bromide(0.147 g) and the mixture was heated at reflux for 2 hours. The solutionwas washed with water, dried over Na₂SO₄, filtered and evaporated. Theresidue was crystallized from diisopropy ether to give the titlecompound (0.21 g) as white crystals.

m.p .: 114-116° C.

Analysis for C32H29FN4O2 C,73.83; H,5.61; N,10.76; C,74.10; H,5.89;N,10.68%.

EXAMPLE 36

4′-Trifluoromethyl-biphenyl-2-carboxylic Acid[3-[4-(3-cyano-benzyl)-piperazin-1-yl]-phenyl]-amide

To a solution of 4′-trifluoromethyl-biphenyl-2-carboxylic acid(3-piperazin-1-yl-phenyl)-amide (0.5 g) in acetone (20 mL) containingK₂CO₃ (0.19 g) was added 3-cyano-benzyl bromide (0.23 g) and the mixturewas heated at reflux for 2 hours. The solution was cooled at roomtemperature and the salts were removed by filtration, washed withacetone and the filtrate was evaporated under reduced pressure. Theresidue was purified by crystallizatiori from AcOEt to give the titlecompound (0.17 g) as white crystals.

m.p.: 170-172° C.

Analysis for C32H27F3N4O Calculated: C,71.10; H,5.03; N,10.36; Found:C,70.69; H,5.15; N,10.18%.

EXAMPLE 37

4′-Trifluoromethyl-biphenyl-2-carboxylic Acid[4-(4-carbamoylrmethyl-piperazin-1-yl)-phenyl]-amide

To a solution of 4′-trifluoromethyl-biphenyl-2-carboxylic acid(4-piperazin-1-yl-phenyl]-amide (0.31 g) in acetone (10 mL) containingK₂CO₃ (0.31 g) was added 2-bromo-acetamide (0.124 g) and the mixture washeated at reflux for 3 hours. After cooling at room temperature thesalts were removed by filtration, washed with acetone and the filtratewas evaporated under reduced pressure. The residue was purified by flashchromatography eluting with CH₂Cl₂/MeOH (95/5) and the solid obtainedwas recrystallized from EtOH to give the title compound (0.23 g) aswhite crystals.

m.p.: 226-228° C.

Analysis for C26H25F3N4O2 Calculated: C,64.72; H,5.22; N,11.61; Found:C,64.69; H,5.45; N,11.59%.

EXAMPLE 38

4′-Isopropyl-4-methoxy-biphenyl-2-carboxylic Acid[4-(4-carbamoylmethyl-piperazin-1-yl)-phenyl]-amide

To a solution of 4′-isopropyl-6-methoxy-biphenyl-2-carboxylic acid(4-piperazin-1-yl-phenyl)-amide (214 mg) in acetone (20 mL) containingK₂CO₃ (206 mg) was added 2-bromo-acetamide (100 mg) and the mixture washeated at reflux for 16 hours. After cooling at room temperature thesalts were removed by filtration, washed with acetone and the filtratewas evaporated under reduced pressure. The residue was purified by flashchromatography eluting with CH₂Cl₂/MeOH (92/8) and the solid obtainedwas recrystallized from CH₂Cl₂/diisopropyl ether to give the titlecompound (120 mg) as white crystals.

m.p.: 207-209° C.

Analysis for C29H34N4O3 Calculated: C,71.58; H,7.04; N,11.51; Found:C,71.68; H,6.47; N,11.44%.

EXAMPLE 39

4′-Isopropyl-6-methyl-biphenyl-2-carboxylic Acid[4-(4-carbamoylmethyl-piperazin-1-yl)-pheny]-amide

To a solution of 4′-isopropyl-6-methyl-biphenyl-2-carboxylic acid(4-piperazin-1-yl-phenyl)-amide (206 mg) in acetone (20 mL) containingK₂CO₃ (206 mg) was added 2-bromo-acetamide (100 mg) and the mixture washeated at reflux for 16 hours. After cooling at room temperature thesalts were removed by filtration, washed with acetone and the filtratewas evaporated under reduced pressure. The residue was purified by flashchromatography eluting with CH₂Cl₂/MeOH (93/7) and the solid obtainedwas recrystallized from CH₂Cl₂/diisopropyl ether to give the titlecompound (190 mg) as white crystals.

m.p.: 181-183° C.

Analysis for C29H34N4O2 Calculated: C,74.01; H,7.28; N,11.91; Found:C,73.87; H,6.69; N,11.84%.

Similarly prepared were:

EXAMPLE 40

6-Methyl-4′-trifluoromethyl-biphenyl-2-carboxylic acid[4-(4-carbamoylmethyl-piperazin-1-yl)-phenyl]-amide as white crystals(100 mg), m.p.: 196-198° C. from6-methyl-4′-trifluoromethyl-biphenyl-2-carboxylic acid(4-piperazin-1-yl-phenyl)-amide (220 mg) and 2-bromo-acetamide (100 mg).

Analysis for C27H27F3N4O2(0.25H₂O) Calculated: C,64.73; H,5.53; N,11.18;Found: C,64.44; H,4.93; N,10.98%.

EXAMPLE 41

4′-Trifluoromethyl-biphenyl-2-carboxylic acid[4-(4-cyanomethyl-piperazin-1-y]-phenyl]-amide as white crystals (1.3g), m.p.: 244-246° C. from 4′-trifluoromethyl-biphenyl-2-carboxylic acid(4-piperazin-1-yl-phenyl)-amide (2.12 g) and chloro-acetonitrile (396mg).

Analysis for C26H23F3N4O (0.25H₂O) Calculated: C,66.59; H,5.05; N,11.95;Found: C,66.51; H,4.89; N,11.81%.

EXAMPLE 42

4′-Trifluoromethyl-biphenyl-2-carboxylic acid[4-(4-ethoxycarbonylmethyl-piperazin-1-yl)-phenyl)-amide as whitecrystals (5.1 g), m.p.: 167-169° C. from4′-trifluoromethyl-biphenyl-2-carboxylic acid(4-piperazin-1-yl-phenyl)-amide (4.25 g) and bromo-acetic acid ethylester (1.83 g).

Analysis for C28H28F3N3O3 Calculated: C,65.74; H,5.52; N,8.21 Found:C,65.76; H,5.09; N,8.16%.

EXAMPLE 43

4′-Trifluoromethyl-biphenyl-2-carboxylic acid[4-(4-(2-ethoxy-ethyl)-piperazin-1-yl]-phenyl]-amide as white crystals(210 mg), m.p.: 176-178° C. from4′-trifluoromethyl-biphenyl-2-carboxylic acid(4-piperazin-1-yl-phenyl)-amide (318 mg) and 1-bromo-2-ethoxy-ethane(126 mg).

Analysis for C28H30F3N3O2 Calculated: C,67.59; H,6.08; N,8.45; Found:C,67.63; H,6.05; N,8.49%.

EXAMPLE 44

4′-Trifluoromethyl-biphenyl-2-carboxylic acid[4-(4-(3-hydroxy-propyl)-piperazin-1-yl]-phenyl]-amide as white crystals(160 mg), m.p.: 208-210° C. from4′-trifluoromethyl-biphenyl-2-carboxylic acid(4-piperazin-1-yl-phenyl)-amide (318 mg) and 3-bromo-propan-1-ol (125mg).

Analysis for C27H28F3N3O2(0.5H₂O) Calculated: C,65.84; H,5.93; N,8.53;Found: C,65.66; H,6.23; N,8.40%.

EXAMPLE 45

4′-Trifluoromethyl-biphenyl-2-carboxylc acid[4-(4-(4,4,4-trifluoro-butyl)-piperazin-1-yl)-phenyl]-amide as whitecrystals (240 mg), m.p.: 198-200° C. from4′-trifluoromethyl-biphenyl-2-carboxylic acid(4-piperazin-1-yl-phenyl)-amide (297 mg) and4-bromo-1,1,1-trifluoro-butane (143 mg).

Analysis for C28H27F6N3O (0.5H₂O) Calculated: C,61.76; H,5.18; N,7.72;Found: C,61.53; H,4.88; N,7.55%.

EXAMPLE 46

4′-Trifluoromethyl-biphenyl-2-carboxylic acidf4-(4-(3-methyl-but-2-enyl)-piperazin-1-yl]-phenyl]-amide as whitecrystals (180 mg), m.p.: 203-205° C. from,4′-trifluoromethyl-biphenyl-2-carboxylic acid(4-piperazin-1-yl-phenyl)-amide (318 mg) and 1-bromo-3-methyl-but-2-ene(122 mg).

Analysis for C29H30F3N3O (0.4H₂O) Calculated: C,69.56; H,6.20; N,8.39;Found: C,69.34; H,5.62; N,8.55%.

EXAMPLE 47

4′-Trifluoromethyl-biphenyl-2-carboxylic acid[4-(4-(3-cyano-4-fluoro-benzyl)-piperazin-1-yl)-phenyl-amide as whitecrystals (440 mg), m.p.: 168-170° C. from4′-trifluoromethyl-biphenyl-2-carboxylic acid(4-piperazin-1-yl-phenyl)-amide (425 mg) and 3-cyano4-fluoro-benzylbromide (214 mg).

Analysis for C32H26F4N4O Calculated: C,68.81; H,4.69; N,10.03; Found:C,68.83; H,4.55; N, 9.98%.

EXAMPLE 48

4′-Trifluoromethyl-biphenyl-2-carboxylic acid[4-(4-(3,4-methylenedioxy-benzyl)-piperazin-1-yl)-phenyl]-amide as whitecrystals (180 mg), m.p.: 189-191° C. from4′-trifluoromethyl-biphenyl-2-carboxylic acid(4-piperazin-1-yl-phenyl)-amide (318 mg) and 3,4-methylenedioxy-benzylchloride (140 mg).

Analysis for C32H28F3N3O3 Calculated: C,68.68; H,5.04; N,7.51; Found:C,68.44; H,5.04; N,7.54%.

EXAMPLE 49

4′-Trifluoromethyl-biphenryl-2-carboxylic acid[4-(4-(3-nitro-benzyl)-piperazin-1-yl)-phenyl]-amide as pale yellowcrystals (900 mg), m.p.: 152-154° C. from4′-trifluoromethyl-biphenyl-2-carboxylic acid(4-piperazin-1-yl-phenyl)-amide (1.06 g) and 3-nitro-benzyl bromide (538mg).

Analysis for C31 H27F3N4O3 Calculated: C,66.42; H,4.85; N,9.99; Found:C,66.02; H,5.03; N,9.95%.

EXAMPLE 50

4′-Trifluoromethyl-biphenyl-2-carboxylic acid{4-[4-(3-carbamoyl-benzyl)-piperazin-1-yl]-phenyl)amide as white cystals(1.5 g), m.p.: 199-201° C. from 4′-trifluoromethyl-biphenyl-2-carboxylicacid (4-piperazin-1-yl-phenyl)-amide (1.7 g) and3-chloromethyl-benzamide (676 mg).

Analysis for C32H29F3N4O2 Calculated: C,68.81; H,5.23; N,10.03; Found:C,68.84; H,5.52; N,9.99%.

Similarly prepared were:

Molecular formula: CHN calc: Example —X—Z—R¹ CHN found: m.p. ° C. Ex 51

C32H30F3N3O2(1 H₂O) C, 68.19; H, 5.72; N, 7.46; C, 68.39; H, 6.03; N,7.07%. 168-170 Ex 52

C31H27F4N3O C, 69.78; H, 5.10; N, 7.88; C, 69.37; H, 5.17; N, 7.84%.198-200 Ex 53

C31H27F4N3O(0.6 H₂O) C, 68.40; H, 5.22; N, 7.72; C, 68.39; H, 5.14; N,7.70%.   189-190.5 Ex 54

C31H28F3N3O(0.2 H₂O) C, 71.72; H, 5.51; N, 8.09; C, 71.43; H, 5.51; N,8.02%. 191-193 Ex 55

C33H30F3N3O3 C, 69.10; H, 5.27; N, 7.33; C, 68.70; H, 5.13; N, 7.10%.190-192 Ex 56

C30H27F3N4O C, 69.76; H, 5.27; N, 10.85; C, 69.67; H, 5.28; N, 10.86%.194-196 Ex 57

C30H27F3N4O(0.5 H₂O) C, 68.56; H, 5.37; N, 10.66; C, 68.46; H, 5.21; N,10.58%. 168-170 Ex 58

C29H26F3N5O C, 67.30; H, 5.06; N, 13.53; C, 66.84; H, 5.07; N, 13.30%.183-185 Ex 59

C28H25F3N4OS(0.25 H₂O) C, 63.80; H, 4.88; N, 10.63; C, 63.69; H, 4.97;N, 10.65%. 187-189 Ex 60

C29H28F3N5O C, 67.04; H, 5.43; N, 13.48; C, 66.52; H, 5.64; N, 13.28%.118-120

EXAMPLE 61

4′-Isopropyl-6-methyl-biphenyl-2-carboxylic Acid(4-(4-(3-(3-methyl-1,2,4]oxadiazol-5-yl)-benzyl)-piperazine-1-yl)-phenyl)-amide

To a solution of 4′-isopropyl-6-miethyl-biphenyl-2-carboxylic acid(4-piperazin-1-yl-phenyl)-amide (309 mg) in 1,2-dichloroethane (20 mL)was added 3-(3-methyl-[1,2,4]oxadiazol-5-yl)-benzaldehyde (154 mg) andacetic acid (67 mg). The solution was cooled at 0° C. and sodiumtriacetoxy borohydride (317 mg) was added portionwise and the mixturewas stirred at room temperature for 16 hours. The solution was thenwashed with a saturated solution of NaHCO₃, with brine, dried overNa₂SO₄, filtered and evaporated under reduced pressure. The residue waspurified by flash chromatography eluting with CH₂Cl₂/MeOH (98/2) and thesolid obtained was recrystallized from CH₂Cl₂/hexane to give the titlecompound (140 mg) as white crystals

m.p.: 74° C.

Analysis for C37H39N5O2(0.5H₂O) Calculated: C,74.72; H,6.78; N,11.78;Found: C,74.39; H,6.74; N,11.73%.

EXAMPLE 62

4′-Trifluormethyl-biphenyl-2-carboxylic Acid[4-(4-(1H-pyrrol-2-ylmethyl)-piperazin-1-yl)-phenyl)-amide

To a solution of 4′-trifluoromethyl-biphenyl-2-carboxylic acid(4-piperazin-1-yl-phenyl)-amide (310 mg) in 1,2-dichloroethane (20 mL)was added 1H-pyrrole-2-carboxaldehyde (95 mg) and acetic acid (67 mg).The solution was cooled at 0° C. and sodium triacetoxy borohydride (317mg) was added portionwise and the mixture was stirred at roomtemperature for 16 hours. The solution was then washed with a saturatedsolution of NaHCO₃, with brine, dried over Na₂SO₄, filtered andevaporated under reduced pressure. The residue was purified by flashchromatography eluting with CH₂Cl₂/MeOH (95/5) and the solid obtainedwas recrystallized from EtOH to give the title compound (180 mg) aswhite crystals.

m.p.: 191-193° C.

Analysis for C29H27F3N4O Calculated: C,69.04; H,5.39; N,11.10; Found:C,69.56; H,5.80; N,11.06%.

EXAMPLE 63

4′-Isopropyl-5-methyl-biphenyl-2-carboxylic Acid[4-(4-(1H-pyrrol-2-ylmethyl)-25 piperazin-1-yl)-phenyl]-amide

To a solution of 4′-isopropyl-5-methyl-biphenyl-2-carboxylic acid(4-piperazin-1-yl-phenyl)-amide (290 mg) in 1,2-dichloroethane (20 mL)was added 1H-pyrrole-2-carboxaldehyde (68 mg) and acetic acid (67 mg).The solution was cooled at 0° C. and sodium triacetoxy borohydride (317mg) was added portionwise and the mixture was stirred at roomtemperature for 16 hours. The solution was then washed with a saturatedsolution of NaHCO₃, with brine, dried over Na₂SO₄, filtered andevaporated under reduced pressure. The residue was purified by flashchromatography eluting with CH₂Cl₂/MeOH (98/2) and the solid obtainedwas recrystallized from MeOH to give the title compound (60 mg) as whitecrystals.

m.p.: 185-187° C.

Analysis for C32H36N4O Calculated: C,78.02; H,7.36; N, 11.37; Found:C,78.35; H,7.11; N,11.27%.

EXAMPLE 64

5-Methyl-4′-trifluoromethyl-biphenyl-2-carboxylic Acid[4-(4-(1H-pyrrol-2-ylmethyl)-piperazin-1-yl)-phenyl]-amide

To a solution of 5-methyl-4′-trifluoromethyl-biphenyl-2-carboxylic acid(4-piperazin-1-yl-phenyl)-amide (329 mg) in 1,2-dichloroethane (20 mL)was added 1H-pyrrole-2-carboxaldehyde (86 mg) and acetic acid (54 mg).The solution was cooled at 0° C. and sodium triacetoxy borohydride (238mg) was added portionwise and the mixture was stirred at roomtemperature for 16 hours. The solution was then washed with a saturatedsolution of NaHCO₃, with brine, dried over Na₂SO₄, filtered andevaporated under reduced pressure. The residue was purified by flashchromatography eluting with CH₂Cl₂/MeOH (95/5) and the oily residueobtained was crystallized from diisopropyl ether to give the titlecompound (210 mg) as white crystals.

m.p.: 196-198° C.

Analysis for C30H29F3N4O(0.5H₂O) Calculated: C,68.30; H,5.73; N,10.62;Found: C,68.05; H,6.03; N, 10.36%.

Similarly prepared were:

EXAMPLE 65

4′-Trifluoromethyl-biphenyl-2-carboxylic acid[4-(4-propyl-piperazin-1-yl)-phenyl]-amide as white crystals (160 mg),m.p .: 207-209° C. from 4′-trifluoromethyl-biphenyl-2-carboxylic acid(4-piperazin-1-yl-phenyl)-amide (0.31 g) and propionaldehyde (64 mg).

Analysis for C27H28F3N3O Calculated: C,69.36; H,6.04; N,8.99; Found;C,69.47; H,6.12; N,8.86%.

EXAMPLE 66

4′-Trifluoromethyl-biphenyl-2-carboxylic acid[4-(4-(3-acetyl-benzyl)-piperazin-1-yl)-phenyl]-amide as white crystals(235 mg), m.p.: 181-183° C. from4′-trifluoromethyl-biphenyl-2-carboxylic acid(4-piperazin-1-yl-phenyl)-amide (0.31 g) and 3-acetyl-benzaldehyde (122mg).

Analysis for C33H30F3N3O2(0.25H₂O) Calculated: C,70.51; H,5.47; N,7.48;Found: C,70.41; H,5.12; N,7.40%.

EXAMPLE 67

4′-Trifluoromethyl-biphenyl-2-carboxylic acid[4-(4-furan-2-ylmethyl-piperazin-1-yl)-phenyl]-amide as a pale yellowsolid (180 mg), m.p.: 173-175° C. from4′-trifluoromethyl-biphenyl-2-carboxylic acid(4-piperazin-1-yl-phenyl)-amide (0.31 g) and furan-2-carboxaldehyde (106mg).

Analysis for C29H26F3N3O2 Calculated: C,68.90; H,5.18; N,8.31; Found:C,69.00; H,5.31; N,8.17%.

EXAMPLE 68

4′-Isopropyl-6-methoxy-biphenyl-2-carboxylic acid[4-(4-(1H-pyrrol-2-ylmethyl)-piperazin-1-yl)-phenyl]-amide as whitecrystals (230 mg), m.p.: 195-197° C. from4′-isopropyl-6-methoxy-biphenyl-2-carboxylic acid(4-piperazin-1-yl-phenyl)-amide (0.3 g) and 1H-pyrrole-2-carboxaldehyde(68.5 mg).

Analysis for C32H36N4O2 Calculated: C,75.56; H,7.13; N,11.01; Found:C,75.79; H,7.16; N,11.03%.

EXAMPLE 69

4′-Trifluoromethyl-biphenyl-2-carboxylic acid[4-(4-(41-methyl-1H-pyrrol-2-ylmethyl)-piperazin-1-yl)-phenyl]-amide aswhite crystals (150 mg), m.p.: 177-179° C. from4′-trifluoromethyl-biphenyl-2-carboxylic acid(4-piperazin-1-yl-phenyl)-amide (0.31 g) and1-methyl-1H-pyrrole-2-carboxaldehyde (109 mg).

Analysis for C30H29F3N4O (1H₂O) Calculated: C,67.15; H,5.82; N,10.44;Found: C,67.45; H,5.70; N,10.51%.

EXAMPLE 70

4′-Trifluoromethyl-biphenyl-2-carboxylic acid[4-(4-thiophen-2-ylmethyl-piperazin-1-yl)-phenyl]-amide as a yellowsolid (150 mg), m.p.: 181-183° C. from4′-trifluoromethyl-biphenyl-2-carboxylic acid(4-piperazin-1-yl-phenyl)-amide (0.31 g) and thiophene-2-carboxaldehyde(126 mg).

Analysis for C29H26F3N3OS (1.25H₂O) Calculated: C,64.01; H,5.28; N,7.72;Found: C,64.05; H,5.04; N,7.72%.

EXAMPLE 71

4′-Trifluoromethyl-biphenyl-2-carboxylic acid{4-[4-(1H-pyrazole-3-ylmethyl)-piperazine-1-yl]-phenyl}-amide as whitecrystals (210 mg), m.p.: 194-196° C. from4′-trifluoromethyl-biphenyl-2-carboxylic acid(4-piperazin-1-yl-phenyl)-amide (0.31 g) and1H-pyrazole-3-carboxaldehyde (79 mg).

MS: m/z 506(M+1).

EXAMPLE 72

4′-Trifluoromethyl-biphenyl-2-carboxylic acid(4-(4-thiophen-3-ylmethyl-piperazin-1-yl)-phenyli-amide as whitecrystals (170 mg), m.p.: 187-189° C. from4′-trifluoromethyl-biphenyl-2-carboxylic acid(4-piperazin-1-yl-phenyl)-amide (0.31 g) and thiophene-3-carboxaldehyde(112 mg).

Analysis for C29H26F3N3OS Calculated: C,66.78; H,5.02; N,8.06; Found:C,67.10; H,5.40; N,8.01%.

EXAMPLE 73

4′-Trifluoromethyl-biphenyl-2-carboxylic acid{4-[4-(5-fluoro-1H-indol-3-ylmethyl)-piperazin-1-yl]-phenyl}-amide aswhite crystals (190 mg), m.p.: 168-170° C. from4′-trifluoromethyl-biphenyl-2-carboxylic acid(4-piperazin-1-yl-phenyl)-amide (318 mg) and5-fluoro-1H-indole-3-carboxaldehyde (135 mg).

Analysis for C33H28F4N4O (0.5H₂O) Calculated: C,68.15; H,5.03; N,9.63;Found: C,67.97; H,5.09; N,9.43%.

EXAMPLE 74

4′-Isopropyl-6-methoxy-biphenyl-2-carboxylic acid(4-(4-(3-(3-methyl-[1,2,4]oxadiazol-5-yl)-benzyl)-piperazine-1-yl)-phenyl)-amideas white crystals (300 mg), m.p.: 180-182° C. from4′-isopropyl-6-methoxy-biphenyl-2-carboxylic acid(4-piperazin-1-yl-phenyl)-amide (0.32 g) and 3-(3-methyl-[1,2,4]oxadiazol-5-yl)-benzaldehyde (154 mg).

Analysis for C37H39N5O3(0.5H₂O) Calculated: C,72.76; H,6.60; N,11.47;Found: C 72.80; H,6.59; N,11.31%.

EXAMPLE 75

4′-Trifluoromethyl-biphenyl-2-carboxylic acid(4-{4-[3-(5-trifluoromethyl-[1,2,4]oxadiazol-3-yl)-benzyl]-piperazin-1-yl}-phenyl)-amideas white crystals (240 mg), m.p.: 188-190° C. from4′-trifluoromethyl-biphenyl-2-carboxylic acid(4-piperazin-1-yl-phenyl)-amide (0.31 g) and3-(5-trifluoromethyl-[1,2,4]oxadiazol-3-yl)-benzaldehyde (198 mg).

Analysis for C34H27F6N5O2 Calculated: C,62.67; H,4.18; N,10.75; Found:C,62.09; H,4.65; N,10.56%.

EXAMPLE 76

(4-{4-[(4′-Trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-piperazin-1-yl)-aceticAcid

To a solution of 4′-trifluoromethyl-biphenyl-2-carboxylic acid[4-(4-ethoxycarbonylmethyl-piperazin-1-yl)-phenyl]-amide (4.6 g) in EtOH(80 mL) was added 1N sodium hydroxide and the mixture was stirred underreflux for 2 hours. The solution was cooled at room temperature,acidified with concentrated HCl and evaporated to dryness. The solidresidue was purified by flash chromatography eluting withCH₂Cl₂/MeOH/Et₃N (70/30/0.2) and the solid was recrystallized from EtOHto give the title compound (4.2 g) as white crystals.

m.p.: 195-197° C.

EXAMPLE 77

4′-Trifluoromethyl-biphenyl-2-carboxylic Acid[4-(4{[(biphenyl-3-ylmethyl)-carbamoyl]-methyl}piperazin-1-yl)-phenyl]-amide

To a stirred solution of(4-{4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-piperazin-1-yl)-aceticacid (241 mg), biphenyl-3-yl-methylamine (95 mg), HOBt (87 mg), and Et₃N(202 mg) in CH₂Cl₂ (20 mL) was added EDCl (125 mg) and the mixture wasstirred at room temperature for 16 hours. The organic solution was thenwashed with water, with a saturated solution of NaHCO₃ and dried overNa₂SO₄. After filtration and evaporation of the filtrate, the residuewas purified by flash chromatography eluting with CH₂Cl₂/MeOH (97/3) andthe solid obtained was recrystallized from EtOH to give the titlecompound (180 mg) as white crystals.

m.p.: 165-167° C.

Analysis for C39H35F3N4O2 Calculated: C,72.21; H,5.44; N,8.64; Found:C,71.94; H,5.66; N,8.53%.

EXAMPLE 78

3-(4-{4-[(4′-Trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-piperazin-1-ylmethyl)-benzoicAcid

To a solution of 4′-trifluoromethyl-biphenyl-2-carboxylic acid[4-[4-(3-carbomethoxy-benzyl)-piperazin-1-yl]-phenyl]-amide (1.6 g) inEtOH (100 mL) was added 1N sodium hydroxide (5.6 mL) and the mixture wasstirred under reflux for 16 hours. The solution was cooled at roomtemperature and acidified with 1N hydrochloric acid (5.6 mL). The whiteprecipitate obtained was filtered and recristallized from EtOH to givethe title compound (1.4 g) as white crystals. m.p.: 225-227° C.

EXAMPLE 79

4′-Trifluoromethyl-biphenyl-2-carboxylic Acid(4-{4-[3-(2,2,2-trifluoro-ethylcarbamoyl)-benzyl]-piperazin-1-yl}-phenyl)-amide

To a stirred solution of3-(4-{4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino)-phenyllpiperazin-1-ylmethyl)-benzoicacid (279 mg), 2,2,2-trifluoro-ethylamine (74 mg), HOBt (85 mg), andEt₃N (63 mg) in CH₂Cl₂ (10 mL) was added EDCl (125 mg) and the mixturewas stirred at room temperature for 48 hours. The organic solution wasthen washed with water, with a saturated solution of NaHCO₃ and driedover Na₂SO₄. After filtration and evaporation of the filtrate, theresidue was purified by flash chromatography eluting with CH₂Cl₂/MeOH(97/3) and the solid obtained was recrystallized from CH2Cl2/diisopropylether to give the title compound (190 mg) as white crystals.

m.p.: 205-207° C.

Analysis for C34H30F6N4O2 Calculated: C,63.75; H,4.72; N,8.75; Found:C,63.65; H,4.95; N,8.63%.

EXAMPLE 80

4′-Trifluoromethyl-biphenyl-2-carboxylic Acid[4-[4-(3-cyano-benzoyl)-piperazin-1-yl]-phenyl]-amide

To a stirred solution of 4′-trifluoromethyl-biphenyl-2-carboxylic acid(4-piperazin-1-yl-phenyl)-amide (0.318 g) in CH₂Cl₂ (15 mL) containingEt₃N (79 mg) was added dropwise 3-cyano-benzoyl chloride (0.129 g) andthe mixture was stirred at room temperature for 1 hour. The solution wasthen washed with water, with brine, dried over Na₂SO₄, filtered andevaporated. The residue was then purified by flash chromatographyeluting with CH₂Cl₂/AcOEt (80/20) and the solid obtained wasrecrystallized from AcOEt to give the title compound (0.29 g) as whitecrystals.

m.p, : 178.5-180° C.

Analysis for C32H25F3N4O2 Calculated: C,69.31; H,4.54; N,10.10; Found:C,69.49; H,4.63; N,10.08%.

EXAMPLE 81

4′-Trifluoromethyl-biphenyl-2-carboxylic Acid[4-(4-acetyl-piperazin-1-yl)-phenyl]-amide

A solution of 4′-trifluoromethyl-biphenyl-2-carboxylic acid(4-piperazin-1-yl-phenyl)-amide (212 mg) in acetic anhydride (10 mL) wasstirred at room temperature for 16 hours. The solution was evaporatedunder reduced pressure, and the residue was dissolved in CH₂Cl₂ andwashed with a saturated solution of NaHCO₃, with brine, dried overNa₂SO₄, filtered and evaporated. The oily residue was crystallized fromAcOEt to give the title compound (130 mg) as white crystals.

m.p.: 175-176.5° C.

Analysis for C26H24F3N3O2 Calculated: C,66.80; H,5.17; N,8.99; Found:C,66.69; H,5.15; N,8.87%.

EXAMPLE 82

4′-Trifluoromethyl-biphenyl-2-carboxylic Acid[4-[4-(3-cyano-benzenesulfonyl)-piperazin-1-yl]-phenyl]-amide

To a stirred solution of 4′-trifluoromethyl-biphenyl-2-carboxylic acid(4-piperazin-1-yl-phenyl)-amide (0.318 g) in CH₂Cl₂ (20 mL) containing.Et₃N (90 mg) was added dropwise 3-cyano-benzenesulfonyl chloride (0.179g) and the mixture was stirred at room temperature for 48 hours. Thesolution was then washed with water, with brine, dried over Na₂SO₄,filtered and evaporated. The residue was then purified by flashchromatography eluting with CH₂Cl₂ to give the title compound (0.39 g)as a white solid.

m.p.: 223° C.

Analysis for C31H25F3N4O3S(0.5H₂O) Calculated: C,62.10; H,4.37; N,9.34;Found: C,62;03; H,4.55; N,9.11%.

EXAMPLE 83

4′-Trifluoromethyl-biphenyl-2-carboxylic Acid[4-(4-methanesulfonyl-piperazin-1-yl)-phenyl]-amide

To a solution of 4′-trifluoromethyl-biphenyl-2-carboxylic acid(4-piperazin-1-yl-phenyl)-amide (318 mg) in CH₂Cl₂ (10 mL) containingEt₃N (91 mg) was added methanesulfonyl chloride (70 μL) and the mixturewas stirred at room temperature for 1 hour. The solution was washed withwater, with brine and dried over Na₂SO₄, filtered and evaporated. Thesolid obtained was recrystallized from CH₃CN to give the title compound(170 mg) as white crystals.

m.p.: 254-256° C.

Analysis for C25H24F3N3O3S Calculated: C,59.63; H,4.80; N,8.34; FoundC,59.58; H,5.10; N,8.57%.

EXAMPLE 84

4′-Trifluoromethyl-biphenyl-2-carboxylic Acid(4-[1-(3-cyano-benzyl)-piperidin-4-yl]-phenyl]-amide

To a solution of 4′-trifluoromethyl-biphenyl-2-carboxylic acid(4-piperidin-4-yl]-phenyl)-amide trifluoroacetate salt. (0.23 g) inacetone (10 mL) containing K₂CO₃ (0.18 g) was added 3-cyano-benzylbromide (0.086 g) and the mixture was heated at reflux. After 16 hours,the mixture was cooled at room temperature, the salts were removed byfiltration, washed with acetone and the filtrate was evaporated underreduced presssure. The residue was purified by flash chromatographyeluting with CH₂Cl₂/MeOH (98/2) and the oily residue was crystallizedfrom diisopropyl ether to give the title compound (0.13 g) as whitecrystals.

m.p.: 124-126° C.

Analysis for C33H28F3N3O Calculated: C,73.45; H,5.23; N,7.79; Found:C,73.43; H,5.56; N,7.91%.

EXAMPLE 85

N-{4-[4-(3-Cyano-benzyl)-piperazin-1-yl]-phenyl}-2-pyrrol-1-yl-benzamideas a pale yellow solid (426 mg), m.p.: 174° C. from2-pyrrol-1-yl-benzoic acid (538 mg) and4-[4-(3-cyano-benzyl)-piperazin-1-yl]-phenylamine (700 mg).

Analysis for C29H27N5O Calculated C,75.46; H,5.90; N,15.17; Found:C,75.09; H,6.07; N,15.15%.

EXAMPLE 86

N-{4-[4-(3-Cyano-benzyl)-piperazin-1-yl]-phenyl}-2-pyridin-2-yl-benzamideas white crystals (200 mg), m.p.: 169-171° C. from2-pyridin-2-yl-benzoic acid (199 mg) and4-[4-(3-cyano-benzyl)-piperazin-1-yl]-phenylamine (292 mg).

Analysis for C30H27N5O Calculated: C,76.09; H,5.75; N,14.79; FoundC,76.04; H,5.94; N,14.47%.

EXAMPLE 87

4′-Trifluoromethyl-biphenyl-2-carboxylic Acid[4-[4-(3-cyano-benzyl)-piperazin-1-yl]-phenyl]-amide Citrate Salt

To a solution of 4′-trifluoromethyl-biphenyl-2-carboxylic acid[4-[4-(3-cyano-benzyl)-piperazin-1-yl]-phenyl]-amide (0.2 g) in MeOH (15mL) was added citric acid (71 mg) and the resulting solution was stirredat room temperature. The solution was then evaporated to dryness and thesolid was triturated in Et₂O, filtered and dried to give the titlecompound (0.15 g) as a white powder.

m.p.: 120° C.

EXAMPLE 88

4′-Trifluoromethl-biphenyl-2-carboxylic Acid[4-[4-(3-cyano-benzyl)-piperazin-1-yl]-phenyl]-amide hydrochloride Salt

To a solution of 4′-trifluoromehtyl-biphenyl-2-carboxylic acid[4-[4-(3-cyano-benzyl)-piperazin-1-yl]-phenyl]-amide (0.2 g) in AcOEt(25 mL) was added 1N hydrochloric acid (0.9 mL) and the resultingsolution was stirred at room temperature for 1.5 hours. The solution wasthen evaporated to dryness and the solid was recrystallized fromAcOEt/hexane to give the title compound (0.18 g) as a white power.

m.p.: 165° C.

Biological Assay

Primary human hepatocytes were seeded at 50 000 cells/well in 96 wellplates. After an overnight adhesion phase, cells were incubated withcompounds for 8 hours in RPMI medium containing 1% FCS, 4 μg/ml insulin,100 nM dexamethasone and 50 μCi/ml ³⁵S-methionine. Compounds weredissolved in DMSO and tested onto cells from 1 μM to 1.6 nM. Productionof radiolabeled apoB-100 and apoA-1 (used as a selectivity control) wasquantified by analysis of supermatants using SDS AGE and exposure ofgels onto Phosphorimager screens. Inhibition of apo-100 and apoA-1secretion by compounds was calculated taking untreated cells ascontrols, and IC₅₀ of each compound was determined on both apoproteins.The following results were obtained for a selection to compounds of theinvention:

Primary human hepatocytes Example no. IC₅₀ (nM) 1 13 3 18 63 20 4 12 313 62 10 2 18 6 18 64 19 5 15

Tablet Compositions

The following compositions A and B can be prepared by wet granulation ofingredients (a) to (c) and (a) to (d) with a solution of povidone,followed by addition of the magnesium stearate and compression.

Composition A mg/tablet mg/tablet (a) Active ingredient 250 250 (b)Lactose B.P. 210 26 (c) Sodium Starch Glycollate 20 12 (d) Povidone B.P.15 9 (e) Magnesium Stearate 5 3 500 300

Composition B mg/tablet mg/tablet (a) Active ingredient 250 250 (b)Lactose 150 150 — (c) Avicel PH 101 60 26 (d) Sodium Starch Glycollate20 12 (e) Povidone B.P. 15 9 (f) Magnesium Stearate 5 3 500 300

Composition C mg/tablet Active ingredient 100 Lactose 200 Starch 50Povidone 5 Magnesium Stearate 4 359

The following compositions D and E can be prepared by direct compressionof the admixed ingredients. The lactose used in composition E is of thedirect compression type.

Composition D mg/tablet Active ingredient 250 Magnesium Stearate 4Pregelatinised Starch NF15 146 400

Composition E mg/tablet Active ingredient 250 Magnesium Stearate 5Lactose 145 Avicel 100 500

Composition F (Controlled release composition) mg/tablet (a) Activeingredient 500 (b) Hydroxypropylmethylcellulose 112 (Methocel K4MPremium) (c) Lactose B.P. 53 (d) Povidone B.P.C. 28 (e) MagnesiumStearate 7 700

The composition can be prepared by wet granulation of ingredients (a) to(c) with a solution of povidone, followed by addition of the magnesiumstearate and compression.

Composition G (Enteric-coated tablet)

Enteric-coated tablets of Composition C can be prepared by coating thetablets with 25 mg/tablet of an enteric polymer such as celluloseacetate phthalate, polyvinylacetate phthalate,hydroxypropylmethyl-cellulose phthalate, or anionic polymers ofmethacrylic acid and methacrylic acid methyl ester (Eudragit L). Exceptfor Eudragit L, these polymers should also include 10% (by weight of thequantity of polymer used) of a plasticizer to prevent membrane crackingduring application or on storage. Suitable plasticizers include diethylphthalate, tributyl citrate and triacetin.

Composition H (Enteric-coated controlled release tablet)

Enteric-coated tablets of Composition F can be prepared by coating thetablets with 50 mg/tablet of an enteric polymer such as celluloseacetate phthalate, polyvinylacetate phthalate,hydroxypropylmethyl-cellulose phthalate, or anionic polymers ofmethacrylic acid and methacrylic acid methyl ester (Eudragit L). Exceptfor Eudragit L, these polymers should also include 10% (by weight of thequantity of polymer used) of a plasticizer to prevent membrane crackingduring application or on storage. Suitable plasticizers include diethylphthalate, tributyl citrate and triacetin.

(ii) Capsule Compositions

Composition A

Capsules can be prepared by admixing the ingredients of Composition Dabove and filling two-part hard gelatin capsules with the resultingmixture. Composition B (infra) may be prepared in a similar manner.

Composition B mg/capsule (a) Active ingredient 250 (b) Lactose B.P. 143(c) Sodium Starch Glycollate 25 (d) Magnesium Stearate 2 420

Composition C mg/capsule (a) Active ingredient 250 (b) Macrogol 4000 BP350 600

Capsules can be prepared by melting the Macrogol 4000 BP, dispersing theactive ingredient in the melt and filling two-part hard gelatin capsulestherewith.

Composition D mg/capsule Active ingredient 250 Lecithin 100 Arachis Oil100 450

Capsules can be prepared by dispersing the active ingredient in thelecithin and arachis oil and filling soft, elastic gelatin capsules withthe dispersion.

Composition E (Controlled release capsule) mg/capsule (a) Activeingredient 250 (b) Microcrystalline Cellulose 125 (c) Lactose BP 125 (d)Ethyl Cellulose 13 513

The controlled release capsule composition can be prepared by extrudingmixed ingredients (a) to (c) using an extruder, then spheronising anddrylng the extrudate. The dried pellets are coated with a releasecontrolling membrane (d) and filled into two-part, hard gelatincapsules.

Composition F (Enteric capsule) mg/capsule (a) Active ingredient 250 (b)Microcrystalline Cellulose 125 (c) Lactose BP 125 (d) Cellulose AcetatePhthalate 50 (e) Diethyl Phthalate 5 555

The enteric capsule composition can be prepared by extruding mixedingredients (a) to (c) using an extruder, then spheronising and drylngthe extrudate. The dried pellets are coated with an enteric membrane (d)containing a plasticizer (e) and filled into two-part, hard gelatincapsules.

Composition G (Enteric-coated controlled release capsule)

Enteric capsules of Composition E can be prepared by coating thecontrolled-release pellets with 50 mg/capsule of an enteric polymer suchas cellulose acetate phthalate, polyvinylacetate phthalate,hydroxypropylmethylcellulose phthalate, or anionic polymers ofmethacrylic acid and methacrylic acid methyl ester (Eudragit L). Exceptfor Eudragit L, these polymers should also include 10% (by weight of thequantity of polymer used) of a plasticizer to prevent membrane crackingduring application or on storage. Suitable plasticizers include diethylphthalate, tributyl citrate and triacetin.

(iii) Intravenous injection composition Active ingredient 0.200 gSterile, pyrogen-free phosphate buffer (pH 9.0) to 10 ml

The active ingredient is dissolved in most of the phosphate buffer at35-40° C., then made up to volume and filtered through a sterilemicropore filter into sterile 10 ml glass vials (Type 1) which aresealed with sterile closures and overseals.

(iv) Intramuscular injection composition Active ingredient 0.20 g BenzylAlcohol 0.10 g Glycofurol 75 1.45 g Water for Injection q.s. to 3.00 ml

The active ingredient is dissolved in the glycofurol. The benzyl alcoholis then added and dissolved, and water added to 3 ml. The mixture isthen filtered through a sterile micropore filter and sealed in sterile 3ml glass vials (Type 1).

(v) Syrup composition Active ingredient 0.25 g Sorbitol Solution 1.50 gGlycerol 1.00 g Sodium Benzoate 0.005 g Flavour 0.0125 ml Purified Waterq.s. to 5.0 ml

The sodium benzoate is dissolved in a portion of the purified water andthe sorbitol solution added. The active ingredient is added anddissolved. The resulting solution is mixed with the glycerol and thenmade up to the required volume with the purified water.

(vi) Suppository composition mg/suppository Active ingredient 250 HardFat, BP (Witepsol H15 - Dynamit NoBel) 1770 2020

One-fifth of the Witepsol H15 is melted in a stearh-jacketed pan at 45°C. maximum. The active ingredient is sifted through a 200 lm sieve andadded to the molten base with mixing, using a Silverson fitted with acutting head, until a smooth dispersion is achieved. Maintaining themixture at 45° C., the remaining Witepsol H15 is added to the suspensionwhich is stirred to ensure a homogenous mix. The entire suspension isthen passed through a 250 lm stainless steel screen and, with continuousstirring, allowed to cool to 40° C. At a temperature of 38-40° C., 2.02g aliquots of the mixture are filled into suitable plastic moulds andthe suppositories allowed to cool to room temperature.

(vii) Pessary composition mg/pessary Active ingredient (631 m) 250Anhydrous Dextrose 380 Potato Starch 363 Magnesium Stearate 7 1000

The above ingredients are mixed directly and pessaries prepared bycompression of the resulting mixture.

(viii) Transdermal composition Active ingredient 200 mg Alcohol USP 0.1ml Hydroxyethyl cellulose

The active ingredient and alcohol USP are gelled with hydroxyethylcellulose and packed in a transdermal device with a surface area of 10cm².

What is claimed is:
 1. A compound of formula (Ie)

wherein R¹ is selected from the following groups (i) aminocarbonyl, (ii)phenyl, optionally substituted by C₁₋₆ alkyl, cyano, halogen,C₁₋₆alkoxy, C₁₋₃perfluoroalkyl, hydroxycarbonyl, C₁₋₄alkoxycarbonyl,aminocarbonyl, methylenedioxy, nitro, C₁₋₆ acyl, phenyl, or anoptionally substituted oxadiazolyl, where optional substitution iseffected by C₁₋₄ alkyl or C₁₋₃perfluoroalkyl, or (iii) an optionallysubstituted aromatic heterocyclyl having monocyclic radicals and fusedpolycyclic radicals, wherein said radicals contain a total of from 5-10ring atoms and are selected from the group consisting of indolyl,pyrrolyl, thienyl, furanyl, imidazolyl, pyrazolyl, thiazolyl, pyridyl,and pyrazinyl, where optional substitution is effected by C₁₋₄ alkyl; R²represents phenyl, optionally substituted by one or two groupsindependently selected from halogen, C₁₋₃perfluoroalkyl, C₁₋₄alkyl andC₁₋₄alkoxy groups; R³ represents hydrogen, halogen, C₁₋₄alkyl orC₁₋₄alkoxy; or a physiologically acceptable salt thereof.
 2. A compoundaccording to claim 1 selected from the group consisting of:4′-Trifluoromethyl-biphenyl-2-carboxylic acid[4-[4-(cyano-benzyl)-piperazin-1-yl]-phenyl]-amide;4′-Isopropyl-5-methyl-biphenyl-2-carboxylic acid[4-[4-(3-cyano-benzyl)-piperazin-1-yl]-phenyl]-amide;4′-Isopropyl-6-methoxy-biphenyl-2-carboxylic acid[4-[4-(3-cyano-benzyl)-piperazin-1-yl]-phenyl]-amide;4′-Isopropyl-4-methyl-biphenyl-2-carboxylic acid[4-[4-(3-cyano-benzyl)-piperazin-1-yl]-phenyl]-amide;6-Methyl-4′-trifluoromethyl-biphenyl-2-carboxylic acid[4-[4-(3-cyano-benzyl)-piperazin-1-yl]-phenyl]-amide;4′-isopropyl-5-methyl-biphenyl-2-carboxylic acid(4-[3-(3-methyl-[1,2,4]oxadiazol-5-yl)-benzyl]-piperazin-1-yl}-phenyl)-amide;5-Chloro-4′-isopropyl-biphenyl-2-carboxylic acid[4-[4-(3-cyano-benzyl)-piperazin-1-yl]-phenyl]-amide;6-Methoxy-4′-trifluoromethyl-biphenyl-2-carboxylic acid[4-[4-(3-cyano-benzyl)-piperazin-1-yl]-phenyl]-amide;5-Methyl-4′-trifluoromethyl-biphenyl-2-carboxylic acid[4-[4-(3-cyano-benzyl)-piperazin-1-yl]-phenyl]-amide;5-Chloro-4′-trifluoromethyl-biphenyl-2-carboxylic acid[4-[4-(3-cyano-benzyl)-piperazin-1-yl]-phenyl]-amide;Biphenyl-2-carboxylic acid[4-[4-(3-cyano-benzyl)-piperazin-1-yl]-phenyl]-amide;5-Methoxy-biphenyl-2-carboxylic acid[4-[4-(3-cyano-benzyl)-piperazin-1-yl]-phenyl]-amide;4-Chloro-4′-trifluoromethyl-biphenyl-2-carboxylic acid[4-[4-(3-cyano-benzyl)-piperazin-1-yl]-phenyl]-amide;4′-Isopropyl-biphenyl-2-carboxylic acid[4-[4(3-cyano-benzyl)-piperazin-1-yl]-phenyl]-amide;5-Methoxy-4′-trifluoromethyl-biphenyl-2-carboxylic acid[4-[4-(3-cyano-benzyl)-piperazin-1yl]-phenyl]-amide; 4-Methyl-4′-trifluoromethyl-biphenyl-2-carboxylic acid[4-[4-(3-cyano-benzyl)-piperazin-1-yl]-phenyl]-amide;4-Methoxy-4′-trifluoromethyl-biphenyl-2-carboxylic acid[4-[4-(3-cyano-benzyl)-piperazin-1-yl]-phenyl]-amide;4′-Ethyl-biphenyl-2-carboxylic acid[4-[4-(3-cyano-benzyl)-piperazin-1-yl]-phenyl]-amide;4′-Methoxy-biphenyl-2-carboxylic acid[4-[4-(3-cyano-benzyl)-piperazin-1-yl]-phenyl]-amide;3′-Trifluoromethyl-biphenyl-2-carboxylic acid[4-[4-(3-cyano-benzyl)-piperazin-1-yl]-phenyl]-amide;4′-Fluoro-biphenyl-2-carboxylic acid[4-[4-(3-cyano-benzyl)-piperazin-1-yl]-phenyl]-amide;3′,4′-Dimethyl-biphenyl-2-carboxylic acid[4-[4-(3-cyano-benzyl)-piperazin-1-yl]-phenyl]-amide;2′,4′-Dimethyl-biphanyl-2-carboxylic acid[4-[4-(3-cyano-benzyl)-piperazin-1-yl]-phenyl]-amide;3′,4′-Dimethoxy-biphenyl-2-carboxylic acid[4-[4-(3-cyano-benzyl)-piperazin-1-yl]-phenyl]-amide;4′-Trifluoromethyl-biphenyl-2-carboxylic acid[3-[4-(3-cyano-benzyl)-piperazin-1-yl-3-phenyl]-amide;4′-Tifluoromethyl-biphenyl-2-carboxylic acid[4-(4-carbamoylmethyl-piperazin-1-yl)-phenyl)-amide;4′-Isopropyl-6-methoxy-biphenyl-2-carboxylic acid[4-(4-carbamoylmethyl-piperazin-1-yl)-phenyl]-amide4′-Isopropyl-6-methyl-biphenyl-2-carboxylic acid[4-(4-carbamoylmethyl-piperazin-1-yl)-phenyl]-amide;6-Methyl-4′-trifluoromethyl-biphenyl-2-carboxylic acid[4-(4-carbamoylmethyl-piperazin-1-yl)-phenyl]-amide;4′-Trifluoromethyl-biphenyl-2-carboxylic acid[4-(4-(3-cyano-4-fluoro-benzyl)-piperazin-1-yl)-phenyl]-amide;4′-Trifluoromethyl-biphenyl-2-carboxylic acid[4-(4-(3,4-methylenedioxy-benzyl)-piperazin-1-yl)-phenyl]-amide;4′-Trifluoromethyl-biphenyl-2-carboxylic acid[4-(4-(3-nitro-benzyl)-piperazin-1-yl)-phenyl]-amide.;4′-Trifluoromethyl-biphenyl-2-carboxylic acid{4-[4-(3-carbamoyl-benzyl)-piperazin-1-yl]-phenyl}-amide;4′-Trifluoromethyl-biphenyl-2-carboxylic acid[4-[4-(3-methoxy-benzyl)-piperazin-1-yl]-phenyl]-amide;4′-Trifluoromethyl-biphenyl-2carboxylic acid[4-[4-(4-fluoro-benzyl)-piperazin-1-yl]-phenyl]-amide;4′-Trifluoromethyl-biphenyl-2-carboxylic acid[4-[4-(3-fluoro-benzyl)-piperazin-1-yl]-phenyl]-amide;4′-Trifluoromethyl-biphenyl-2-carboxylic acid[4-(4-benzyl)-piperazin-1-yl]-phenyl]-amide;4′-Trifluoromethyl-biphenyl-2-carboxylic acid[4-[4-(3-carbomethoxy-benzyl)-piperazin-1-yl]-phenyl]-amide;4′-Trifluoromethyl-biphenyl-2-carboxylic acid[4-(4-pyridin-4-ylmethyl-piperazin-1-yl)-phenyl]-amide;4′-Trifluoromethyl-biphenyl-2-carboxylic acid[4-(4-pyridin-2-ylmethyl-piperazin-1-yl)-phenyl]-amide;4′-Trifluoromethyl-biphenyl-2-carboxylic acid[4-(4-pyrazin-2-ylmethyl-piperazin-1-yl)-phenyl]-amide;4′-Trifluoromethyl-biphenyl-2-carboxylic acid[4-(4-thiazol-2-ylmethyl-piperazin-1-yl)-phenyl]-amide;4′-Trifluoromethyl-biphenyl-2-carboxylic acid[4-[4-(1-methyl-1H-imidazol-2-ylmethyl)-piperazin-1-yl)-phenyl]-amide;4′-Isopropyl-6methyl-biphenyl-2-carboxylic acid(4-(4-(3-(3-methyl-[1,2,4]oxadiazol-5-yl)-benzyl)-piperazine-1-yl)-phenyl)-amide;4′-Trifluoromethyl-biphenyl-2-carboxylic acid[4-(4-(1H-pyrrol-2-ylmethyl)-piperazin-1-yl)-phenyl]-amide;4′-Isopropyl-5-methyl-biphenyl-2-carboxyllc acid[4-(4-(1H-pyrrol-2-ylmethyl)-piperazin-1-yl)-phenyl]-amide;5-Methyl-4′-trifluoromethyl-biphenyl-2-carboxylic acid[4-(4-(1H-pyrrol-2-ylmethyl)-piperazin-1-yl)-phenyl]-amide;4′-Trifluoromethyl-biphenyl-2-carboxylic acid[4-(4-(3-acetyl-benzyl)-piperazin-1-yl)-phenyl]-amide;4′-Trifluoromethyl-biphenyl-2-carboxylic acid[4-(4-furan-2-ylmethyl-piperazin-1-yl)-phenyl]-amide;4′-Isopropyl-6-methoxy-biphenyl-2-carboxylic acid[4-(4-(1H-pyrrol-2-ylmethyl)-piperazin-1-yl)-phenyl)-amide;4′-Trifluoromethyl-biphenyl-2-carboxylic acid[4-(4-(1-methyl-1H-pyrrol-2-ylmethyl)-piperazin-1-yl)-phenyl]-amide;4′-Trifluoromethyl-biphenyl-2-carboxylic acid[4-(4-thiophen-2-ylmethyl-piperazin-1-yl)-phenyl]-amide;4′-Trifluoromethyl-biphenyl-2-carboxylic acid{4-[4-(1H-pyrazole-3-ylmethyl)-piperazine-1-yl]-phenyl}-amide;4′-Trifluoromethyl-biphenyl-2-carboxylic acid[4-(4-thiophen-3-ylmethyl-piperazin-1-yl)-phenyl]-amide;4′-Trifluoromethyl-biphenyl-2-carboxylic acid{4-[4-(5-fluoro-1H-indol-3-ylmethyl)-piperazin-1-yl]-phenyl}-amide;4′-Isopropyl-6-methoxy′-biphenyl-2-carboxylic acid(4-(4-(3-(3-methyl-[1,2,4]oxadiazol-5-yl)-benzyl)-piperazine-1-yl)-phenyl)-amide;4′-Trifluoromethyl-biphenyl-2-carboxylic acid(4-{4-[3-(5-trifluoromethyl-1,2,4]oxadiazol-3-yl)-benzyl]-piperazin-1-yl}-phenyl)-amide;or a physiologically acceptable salt thereof.
 3. A compound according toclaim 2 selected from the group consistin of:4′-Trifluoromethyl-biphenyl-2-carboxylic acid[4-[4-(3-cyano-benzyl)-piperazin-1-yl]-phenyl]-amide;4′-Isopropyl-5-methyl-biphenyl-2-carboxylic acid[4-[4-(3-cyano-benzyl)-piperazin-1-yl]-phenyl]-amide;4′-Isopropyl-6-methoxy-biphenyl-2-carboxylic acid[4-[4-(3-cyano-benzyl)-piperazin-1-yl]-phenyl]-amide4′-Isopropyl-6-methyl-biphenyl-2-carboxylic acid[4-[4-(3-cyano-benzyl)-piperazin-1-yl]-phenyl]-amide;6-Methyl-4′-trifluoromethyl-biphenyl-2-carboxylic acid[4-[4-(3-cyano-benzyl)-piperazin-1-yl]-phenyl]-amide;4′-Isopropyl-5-methyl-biphenyl-2-carboxylic acid(4-{3-(3-methyl-[1,2,4]oxadiazol-5-yl)-benzyl]-piperazin-1-yl}-phenyl)-amide;4′-Trifluoromethyl-biphenyl-2-carboxylic acid[4-(4-carbamoylmethyl-piperazin-1-yl)-phenyl]-amide;4′-Isopropyl-6-methoxy-biphenyl-2-carboxylic acid[4-(4-carbamoylmethyl-piperazin-1-yl)-phenyl]-amide;4′-Isopropyl-6-methyl-biphenyl-2-carboxylic acid[4-(4-carbamoylmethyl-piperazin-1-yl)-phenyl]-amide;4′-Isopropyl-6-methyl-biphenyl-2-carboxylic acid(4-(4-(3-(3-methyl-[1,2,4]oxadiazol-5-yl)-benzyl)-piperazine-1-yl)-phenyl)-amide;4′-Trifluoromethyl-biphenyl-2-carboxylic acid[4-(4-(1H-pyrrol-2-ylmethyl)-piperazin-1-yl)-phenyl]-amide;4′-Isopropyl-5-methyl-biphenyl-2-carboxylic acid[4-(4-(1H-pyrrol-2-ylmethyl)-piperazin-1-yl)-phenyl]-amide;5-Methyl-4′-trifluoromethyl-biphenyl-2-carboxylic acid[4-(4-(1H-pyrrol-2-ylmethyl)-piperazin-1-yl)-phenyl]-amide; or aphysiologically acceptable salt thereof.
 4. A pharmaceutical compositioncomprising a compound according to claim 1 or a physiologicallyacceptable salt thereof together with one or more pharmaceuticallyacceptable carriers.
 5. A process for the preparation of a compoundaccording to claim 1 comprising: reacting a compound of formula (II)with a compound of formula R¹—CH₂—L

 where L represents a halide leaving group.
 6. A method for thetreatment of atherosclerosis in a mammal, said method comprisingadministering an effective amount of a compound according to claim
 1. 7.A method for the treatment of pancreatitis in a mammal, said methodcomprising administering an effective amount of a compound according toclaim
 1. 8. A method for the treatment of non-insulin dependent diabetesmellitus in a mammal, said method comprising administering an effectiveamount of a compound according to claim
 1. 9. A method for the treatmentof coronary heart disease in a mammal, said method comprisingadministering an effective amount of a compound according to claim 1.10. A method for lowering serum lipid levels in a mammal in needthereof, said method comprising administering an effective amount of acompound according to claim
 1. 11. A method for treating a conditionassociated with elevated serum lipid levels in a mammal, said methodcomprising administering an effective amount of a compound according toclaim
 1. 12. The method according to claim 11, wherein the conditionassociated with elevated serum lipid levels is selected from the groupconsisting of hyperlipemia, hyperlipidemia, hyperlipoproteinemia,hypercholesterolemia, and hypertriglyceridemia.